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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Immunological profiling of molecularly classified high-risk endometrial cancers identifies <italic>POLE</italic>-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition</title><author><name sortKey="Eggink, Florine A" sort="Eggink, Florine A" uniqKey="Eggink F" first="Florine A." last="Eggink">Florine A. Eggink</name><affiliation><nlm:aff id="af0001"><institution>Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen</institution>, Groningen,<country>the Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Van Gool, Inge C" sort="Van Gool, Inge C" uniqKey="Van Gool I" first="Inge C." last="Van Gool">Inge C. Van Gool</name><affiliation><nlm:aff id="af0002"><institution>Department of Pathology, Leiden University Medical Center</institution>, Leiden,<country>the Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Leary, Alexandra" sort="Leary, Alexandra" uniqKey="Leary A" first="Alexandra" last="Leary">Alexandra Leary</name><affiliation><nlm:aff id="af0003"><institution>Department of Medical Oncology, INSERM U981, Gustave Roussy Cancer Center</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Pollock, Pamela M" sort="Pollock, Pamela M" uniqKey="Pollock P" first="Pamela M." last="Pollock">Pamela M. Pollock</name><affiliation><nlm:aff id="af0004"><institution>Queensland University of Technology (QUT), Translational Research Institute</institution>, Brisbane, QLD,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Crosbie, Emma J" sort="Crosbie, Emma J" uniqKey="Crosbie E" first="Emma J." last="Crosbie">Emma J. Crosbie</name><affiliation><nlm:aff id="af0005"><institution>Institute of Cancer Sciences, University of Manchester, St Marys Hospital</institution>, Manchester,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Mileshkin, Linda" sort="Mileshkin, Linda" uniqKey="Mileshkin L" first="Linda" last="Mileshkin">Linda Mileshkin</name><affiliation><nlm:aff id="af0006"><institution>Division of Cancer Medicine, Peter MacCallum Cancer Centre</institution>, East Melbourne, VIC,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Jordanova, Ekaterina S" sort="Jordanova, Ekaterina S" uniqKey="Jordanova E" first="Ekaterina S." last="Jordanova">Ekaterina S. Jordanova</name><affiliation><nlm:aff id="af0002"><institution>Department of Pathology, Leiden University Medical Center</institution>, Leiden,<country>the Netherlands</country></nlm:aff></affiliation><affiliation><nlm:aff id="af0007"><institution>Center for Gynecological Oncology Amsterdam, VU Medical Center</institution>, Amsterdam,<country>the Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Adam, Julien" sort="Adam, Julien" uniqKey="Adam J" first="Julien" last="Adam">Julien Adam</name><affiliation><nlm:aff id="af0003"><institution>Department of Medical Oncology, INSERM U981, Gustave Roussy Cancer Center</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Freeman Mills, Luke" sort="Freeman Mills, Luke" uniqKey="Freeman Mills L" first="Luke" last="Freeman-Mills">Luke Freeman-Mills</name><affiliation><nlm:aff id="af0008"><institution>Tumour Genomics and Immunology Group, Oxford Centre for Cancer Gene Research, The Wellcome Trust Centre for Human Genetics, University of Oxford</institution>, Oxford,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Church, David N" sort="Church, David N" uniqKey="Church D" first="David N." last="Church">David N. Church</name><affiliation><nlm:aff id="af0008"><institution>Tumour Genomics and Immunology Group, Oxford Centre for Cancer Gene Research, The Wellcome Trust Centre for Human Genetics, University of Oxford</institution>, Oxford,<country>UK</country></nlm:aff></affiliation><affiliation><nlm:aff id="af0009"><institution>Oxford Cancer Centre, Churchill Hospital</institution>, Oxford,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Creutzberg, Carien L" sort="Creutzberg, Carien L" uniqKey="Creutzberg C" first="Carien L." last="Creutzberg">Carien L. Creutzberg</name><affiliation><nlm:aff id="af0010"><institution>Department of Clinical Oncology, Leiden University Medical Center</institution>, Leiden,<country>the Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="De Bruyn, Marco" sort="De Bruyn, Marco" uniqKey="De Bruyn M" first="Marco" last="De Bruyn">Marco De Bruyn</name><affiliation><nlm:aff id="af0001"><institution>Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen</institution>, Groningen,<country>the Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Nijman, Hans W" sort="Nijman, Hans W" uniqKey="Nijman H" first="Hans W." last="Nijman">Hans W. Nijman</name><affiliation><nlm:aff id="af0001"><institution>Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen</institution>, Groningen,<country>the Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Bosse, Tjalling" sort="Bosse, Tjalling" uniqKey="Bosse T" first="Tjalling" last="Bosse">Tjalling Bosse</name><affiliation><nlm:aff id="af0002"><institution>Department of Pathology, Leiden University Medical Center</institution>, Leiden,<country>the Netherlands</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28344870</idno><idno type="pmc">5353925</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353925</idno><idno type="RBID">PMC:5353925</idno><idno type="doi">10.1080/2162402X.2016.1264565</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">002823</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002823</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Immunological profiling of molecularly classified high-risk endometrial cancers identifies <italic>POLE</italic>-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition</title><author><name sortKey="Eggink, Florine A" sort="Eggink, Florine A" uniqKey="Eggink F" first="Florine A." last="Eggink">Florine A. Eggink</name><affiliation><nlm:aff id="af0001"><institution>Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen</institution>, Groningen,<country>the Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Van Gool, Inge C" sort="Van Gool, Inge C" uniqKey="Van Gool I" first="Inge C." last="Van Gool">Inge C. Van Gool</name><affiliation><nlm:aff id="af0002"><institution>Department of Pathology, Leiden University Medical Center</institution>, Leiden,<country>the Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Leary, Alexandra" sort="Leary, Alexandra" uniqKey="Leary A" first="Alexandra" last="Leary">Alexandra Leary</name><affiliation><nlm:aff id="af0003"><institution>Department of Medical Oncology, INSERM U981, Gustave Roussy Cancer Center</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Pollock, Pamela M" sort="Pollock, Pamela M" uniqKey="Pollock P" first="Pamela M." last="Pollock">Pamela M. Pollock</name><affiliation><nlm:aff id="af0004"><institution>Queensland University of Technology (QUT), Translational Research Institute</institution>, Brisbane, QLD,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Crosbie, Emma J" sort="Crosbie, Emma J" uniqKey="Crosbie E" first="Emma J." last="Crosbie">Emma J. Crosbie</name><affiliation><nlm:aff id="af0005"><institution>Institute of Cancer Sciences, University of Manchester, St Marys Hospital</institution>, Manchester,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Mileshkin, Linda" sort="Mileshkin, Linda" uniqKey="Mileshkin L" first="Linda" last="Mileshkin">Linda Mileshkin</name><affiliation><nlm:aff id="af0006"><institution>Division of Cancer Medicine, Peter MacCallum Cancer Centre</institution>, East Melbourne, VIC,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Jordanova, Ekaterina S" sort="Jordanova, Ekaterina S" uniqKey="Jordanova E" first="Ekaterina S." last="Jordanova">Ekaterina S. Jordanova</name><affiliation><nlm:aff id="af0002"><institution>Department of Pathology, Leiden University Medical Center</institution>, Leiden,<country>the Netherlands</country></nlm:aff></affiliation><affiliation><nlm:aff id="af0007"><institution>Center for Gynecological Oncology Amsterdam, VU Medical Center</institution>, Amsterdam,<country>the Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Adam, Julien" sort="Adam, Julien" uniqKey="Adam J" first="Julien" last="Adam">Julien Adam</name><affiliation><nlm:aff id="af0003"><institution>Department of Medical Oncology, INSERM U981, Gustave Roussy Cancer Center</institution>, Villejuif,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Freeman Mills, Luke" sort="Freeman Mills, Luke" uniqKey="Freeman Mills L" first="Luke" last="Freeman-Mills">Luke Freeman-Mills</name><affiliation><nlm:aff id="af0008"><institution>Tumour Genomics and Immunology Group, Oxford Centre for Cancer Gene Research, The Wellcome Trust Centre for Human Genetics, University of Oxford</institution>, Oxford,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Church, David N" sort="Church, David N" uniqKey="Church D" first="David N." last="Church">David N. Church</name><affiliation><nlm:aff id="af0008"><institution>Tumour Genomics and Immunology Group, Oxford Centre for Cancer Gene Research, The Wellcome Trust Centre for Human Genetics, University of Oxford</institution>, Oxford,<country>UK</country></nlm:aff></affiliation><affiliation><nlm:aff id="af0009"><institution>Oxford Cancer Centre, Churchill Hospital</institution>, Oxford,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Creutzberg, Carien L" sort="Creutzberg, Carien L" uniqKey="Creutzberg C" first="Carien L." last="Creutzberg">Carien L. Creutzberg</name><affiliation><nlm:aff id="af0010"><institution>Department of Clinical Oncology, Leiden University Medical Center</institution>, Leiden,<country>the Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="De Bruyn, Marco" sort="De Bruyn, Marco" uniqKey="De Bruyn M" first="Marco" last="De Bruyn">Marco De Bruyn</name><affiliation><nlm:aff id="af0001"><institution>Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen</institution>, Groningen,<country>the Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Nijman, Hans W" sort="Nijman, Hans W" uniqKey="Nijman H" first="Hans W." last="Nijman">Hans W. Nijman</name><affiliation><nlm:aff id="af0001"><institution>Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen</institution>, Groningen,<country>the Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Bosse, Tjalling" sort="Bosse, Tjalling" uniqKey="Bosse T" first="Tjalling" last="Bosse">Tjalling Bosse</name><affiliation><nlm:aff id="af0002"><institution>Department of Pathology, Leiden University Medical Center</institution>, Leiden,<country>the Netherlands</country></nlm:aff></affiliation></author></analytic><series><title level="j">Oncoimmunology</title><idno type="ISSN">2162-4011</idno><idno type="eISSN">2162-402X</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>ABSTRACT</title><p>High-risk endometrial cancer (EC) is an aggressive disease for which new therapeutic options are needed. Aims of this study were to validate the enhanced immune response in highly mutated ECs and to explore immune profiles in other EC subgroups. We evaluated immune infiltration in 116 high-risk ECs from the TransPORTEC consortium, previously classified into four molecular subtypes: (i) ultramutated <italic>POLE</italic> exonuclease domain-mutant ECs (<italic>POLE</italic>-mutant); (ii) hypermutated microsatellite unstable (MSI); (iii) p53-mutant; and (iv) no specific molecular profile (NSMP). Within The Cancer Genome Atlas (TCGA) EC cohort, significantly higher numbers of predicted neoantigens were demonstrated in <italic>POLE</italic>-mutant and MSI tumors compared with NSMP and p53-mutants. This was reflected by enhanced immune expression and infiltration in <italic>POLE</italic>-mutant and MSI tumors in both the TCGA cohort (mRNA expression) and the TransPORTEC cohort (immunohistochemistry) with high infiltration of CD8<sup>+</sup> (90% and 69%), PD-1<sup>+</sup> (73% and 69%) and PD-L1<sup>+</sup> immune cells (100% and 71%). Notably, a subset of p53-mutant and NSMP cancers was characterized by signs of an antitumor immune response (43% and 31% of tumors with high infiltration of CD8<sup>+</sup> cells, respectively), despite a low number of predicted neoantigens. In conclusion, the presence of enhanced immune infiltration, particularly high numbers of PD-1 and PD-L1 positive cells, in highly mutated, neoantigen-rich <italic>POLE</italic>-mutant and MSI endometrial tumors suggests sensitivity to immune checkpoint inhibitors.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Herbst, Rs" uniqKey="Herbst R">RS Herbst</name></author><author><name sortKey="Soria, J C" uniqKey="Soria J">J-C Soria</name></author><author><name sortKey="Kowanetz, M" uniqKey="Kowanetz M">M Kowanetz</name></author><author><name sortKey="Fine, Gd" uniqKey="Fine G">GD Fine</name></author><author><name sortKey="Hamid, O" uniqKey="Hamid O">O Hamid</name></author><author><name sortKey="Gordon, Ms" uniqKey="Gordon M">MS Gordon</name></author><author><name sortKey="Sosman, Ja" uniqKey="Sosman J">JA Sosman</name></author><author><name sortKey="Mcdermott, Df" uniqKey="Mcdermott D">DF McDermott</name></author><author><name sortKey="Powderly, Jd" uniqKey="Powderly J">JD Powderly</name></author><author><name sortKey="Gettinger, Sn" uniqKey="Gettinger S">SN Gettinger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hodi, Fs" uniqKey="Hodi F">FS Hodi</name></author><author><name sortKey="O Day, Sj" uniqKey="O Day S">SJ O'Day</name></author><author><name sortKey="Mcdermott, Df" uniqKey="Mcdermott D">DF McDermott</name></author><author><name sortKey="Weber, Rw" uniqKey="Weber R">RW Weber</name></author><author><name sortKey="Sosman, Ja" uniqKey="Sosman J">JA Sosman</name></author><author><name sortKey="Haanen, Jb" uniqKey="Haanen J">JB Haanen</name></author><author><name sortKey="Gonzalez, R" uniqKey="Gonzalez R">R Gonzalez</name></author><author><name sortKey="Robert, C" uniqKey="Robert C">C Robert</name></author><author><name sortKey="Schadendorf, D" uniqKey="Schadendorf D">D Schadendorf</name></author><author><name sortKey="Hassel, Jc" uniqKey="Hassel J">JC Hassel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Le, Dt" uniqKey="Le D">DT Le</name></author><author><name sortKey="Uram, Jn" uniqKey="Uram J">JN Uram</name></author><author><name sortKey="Wang, H" uniqKey="Wang H">H Wang</name></author><author><name sortKey="Bartlett, Br" uniqKey="Bartlett B">BR Bartlett</name></author><author><name sortKey="Kemberling, H" uniqKey="Kemberling H">H Kemberling</name></author><author><name sortKey="Eyring, Ad" uniqKey="Eyring A">AD Eyring</name></author><author><name sortKey="Skora, Ad" uniqKey="Skora A">AD Skora</name></author><author><name sortKey="Luber, Bs" uniqKey="Luber B">BS Luber</name></author><author><name sortKey="Azad, Ns" uniqKey="Azad N">NS Azad</name></author><author><name sortKey="Laheru, D" uniqKey="Laheru D">D Laheru</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Powles, T" uniqKey="Powles T">T Powles</name></author><author><name sortKey="Eder, Jp" uniqKey="Eder J">JP Eder</name></author><author><name sortKey="Fine, Gd" uniqKey="Fine G">GD Fine</name></author><author><name sortKey="Braiteh, Fs" uniqKey="Braiteh F">FS Braiteh</name></author><author><name sortKey="Loriot, Y" uniqKey="Loriot Y">Y Loriot</name></author><author><name sortKey="Cruz, C" uniqKey="Cruz C">C Cruz</name></author><author><name sortKey="Bellmunt, J" uniqKey="Bellmunt J">J Bellmunt</name></author><author><name sortKey="Burris, Ha" uniqKey="Burris H">HA Burris</name></author><author><name sortKey="Petrylak, Dp" uniqKey="Petrylak D">DP Petrylak</name></author><author><name sortKey="Teng, S" uniqKey="Teng S">S Teng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hamid, O" uniqKey="Hamid O">O Hamid</name></author><author><name sortKey="Robert, C" uniqKey="Robert C">C Robert</name></author><author><name sortKey="Daud, A" uniqKey="Daud A">A Daud</name></author><author><name sortKey="Hodi, Fs" uniqKey="Hodi F">FS Hodi</name></author><author><name sortKey="Hwu, W J" uniqKey="Hwu W">W-J Hwu</name></author><author><name sortKey="Kefford, R" uniqKey="Kefford R">R Kefford</name></author><author><name sortKey="Wolchok, Jd" uniqKey="Wolchok J">JD Wolchok</name></author><author><name sortKey="Hersey, P" uniqKey="Hersey P">P Hersey</name></author><author><name sortKey="Joseph, Rw" uniqKey="Joseph R">RW Joseph</name></author><author><name sortKey="Weber, Js" uniqKey="Weber J">JS Weber</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Borghaei, H" uniqKey="Borghaei H">H Borghaei</name></author><author><name sortKey="Paz Ares, L" uniqKey="Paz Ares L">L Paz-Ares</name></author><author><name sortKey="Horn, L" uniqKey="Horn L">L Horn</name></author><author><name sortKey="Spigel, Dr" uniqKey="Spigel D">DR Spigel</name></author><author><name sortKey="Steins, M" uniqKey="Steins M">M Steins</name></author><author><name sortKey="Ready, Ne" uniqKey="Ready N">NE Ready</name></author><author><name sortKey="Chow, Lq" uniqKey="Chow L">LQ Chow</name></author><author><name sortKey="Vokes, Ee" uniqKey="Vokes E">EE Vokes</name></author><author><name sortKey="Felip, E" uniqKey="Felip E">E Felip</name></author><author><name sortKey="Holgado, E" uniqKey="Holgado E">E Holgado</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bouffet, E" uniqKey="Bouffet E">E Bouffet</name></author><author><name sortKey="Larouche, V" uniqKey="Larouche V">V Larouche</name></author><author><name sortKey="Campbell, Bb" uniqKey="Campbell B">BB Campbell</name></author><author><name sortKey="Merico, D" uniqKey="Merico D">D Merico</name></author><author><name sortKey="De Borja, R" uniqKey="De Borja R">R de Borja</name></author><author><name sortKey="Aronson, M" uniqKey="Aronson M">M Aronson</name></author><author><name sortKey="Durno, C" uniqKey="Durno C">C Durno</name></author><author><name sortKey="Krueger, J" uniqKey="Krueger J">J Krueger</name></author><author><name sortKey="Cabric, V" uniqKey="Cabric V">V Cabric</name></author><author><name sortKey="Ramaswamy, V" uniqKey="Ramaswamy V">V Ramaswamy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brown, Sd" uniqKey="Brown S">SD Brown</name></author><author><name sortKey="Warren, Rl" uniqKey="Warren R">RL Warren</name></author><author><name sortKey="Gibb, Ea" uniqKey="Gibb E">EA Gibb</name></author><author><name sortKey="Martin, Sd" uniqKey="Martin S">SD Martin</name></author><author><name sortKey="Spinelli, Jj" uniqKey="Spinelli J">JJ Spinelli</name></author><author><name sortKey="Nelson, Bh" uniqKey="Nelson B">BH Nelson</name></author><author><name sortKey="Holt, Ra" uniqKey="Holt R">RA Holt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rooney, Ms" uniqKey="Rooney M">MS Rooney</name></author><author><name sortKey="Shukla, Sa" uniqKey="Shukla S">SA Shukla</name></author><author><name sortKey="Wu, Cj" uniqKey="Wu C">CJ Wu</name></author><author><name sortKey="Getz, G" uniqKey="Getz G">G Getz</name></author><author><name sortKey="Hacohen, N" uniqKey="Hacohen N">N Hacohen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Giannakis, M" uniqKey="Giannakis M">M Giannakis</name></author><author><name sortKey="Mu, Xj" uniqKey="Mu X">XJ Mu</name></author><author><name sortKey="Shukla, Sa" uniqKey="Shukla S">SA Shukla</name></author><author><name sortKey="Qian, Zr" uniqKey="Qian Z">ZR Qian</name></author><author><name sortKey="Cohen, O" uniqKey="Cohen O">O Cohen</name></author><author><name sortKey="Nishihara, R" uniqKey="Nishihara R">R Nishihara</name></author><author><name sortKey="Bahl, S" uniqKey="Bahl S">S Bahl</name></author><author><name sortKey="Cao, Y" uniqKey="Cao Y">Y Cao</name></author><author><name sortKey="Amin Mansour, A" uniqKey="Amin Mansour A">A Amin-Mansour</name></author><author><name sortKey="Yamauchi, M" uniqKey="Yamauchi M">M Yamauchi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pardoll, Dm" uniqKey="Pardoll D">DM Pardoll</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rizvi, Na" uniqKey="Rizvi N">NA Rizvi</name></author><author><name sortKey="Hellmann, Md" uniqKey="Hellmann M">MD Hellmann</name></author><author><name sortKey="Snyder, A" uniqKey="Snyder A">A Snyder</name></author><author><name sortKey="Kvistborg, P" uniqKey="Kvistborg P">P Kvistborg</name></author><author><name sortKey="Makarov, V" uniqKey="Makarov V">V Makarov</name></author><author><name sortKey="Havel, Jj" uniqKey="Havel J">JJ Havel</name></author><author><name sortKey="Lee, W" uniqKey="Lee W">W Lee</name></author><author><name sortKey="Yuan, J" uniqKey="Yuan J">J Yuan</name></author><author><name sortKey="Wong, P" uniqKey="Wong P">P Wong</name></author><author><name sortKey="Ho, Ts" uniqKey="Ho T">TS Ho</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Snyder, A" uniqKey="Snyder A">A Snyder</name></author><author><name sortKey="Makarov, V" uniqKey="Makarov V">V Makarov</name></author><author><name sortKey="Merghoub, T" uniqKey="Merghoub T">T Merghoub</name></author><author><name sortKey="Yuan, J" uniqKey="Yuan J">J Yuan</name></author><author><name sortKey="Zaretsky, Jm" uniqKey="Zaretsky J">JM Zaretsky</name></author><author><name sortKey="Desrichard, A" uniqKey="Desrichard A">A Desrichard</name></author><author><name sortKey="Walsh, La" uniqKey="Walsh L">LA Walsh</name></author><author><name sortKey="Postow, Ma" uniqKey="Postow M">MA Postow</name></author><author><name sortKey="Wong, P" uniqKey="Wong P">P Wong</name></author><author><name sortKey="Ho, Ts" uniqKey="Ho T">TS Ho</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chan, Ta" uniqKey="Chan T">TA Chan</name></author><author><name sortKey="Wolchok, Jd" uniqKey="Wolchok J">JD Wolchok</name></author><author><name sortKey="Snyder, A" uniqKey="Snyder A">A Snyder</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zou, W" uniqKey="Zou W">W Zou</name></author><author><name sortKey="Wolchok, Jd" uniqKey="Wolchok J">JD Wolchok</name></author><author><name sortKey="Chen, L" uniqKey="Chen L">L Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tumeh, P" uniqKey="Tumeh P">P Tumeh</name></author><author><name sortKey="Harview, C" uniqKey="Harview C">C Harview</name></author><author><name sortKey="Yearley, J" uniqKey="Yearley J">J Yearley</name></author><author><name sortKey="Al, E" uniqKey="Al E">E Al</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mlecnik, B" uniqKey="Mlecnik B">B Mlecnik</name></author><author><name sortKey="Bindea, G" uniqKey="Bindea G">G Bindea</name></author><author><name sortKey="Angell, Hk" uniqKey="Angell H">HK Angell</name></author><author><name sortKey="Maby, P" uniqKey="Maby P">P Maby</name></author><author><name sortKey="Angelova, M" uniqKey="Angelova M">M Angelova</name></author><author><name sortKey="Tougeron, D" uniqKey="Tougeron D">D Tougeron</name></author><author><name sortKey="Church, Se" uniqKey="Church S">SE Church</name></author><author><name sortKey="Lafontaine, L" uniqKey="Lafontaine L">L Lafontaine</name></author><author><name sortKey="Fischer, M" uniqKey="Fischer M">M Fischer</name></author><author><name sortKey="Fredriksen, T" uniqKey="Fredriksen T">T Fredriksen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Becht, E" uniqKey="Becht E">E Becht</name></author><author><name sortKey="Giraldo, Na" uniqKey="Giraldo N">NA Giraldo</name></author><author><name sortKey="Germain, C" uniqKey="Germain C">C Germain</name></author><author><name sortKey="De Reynies, A" uniqKey="De Reynies A">A de Reyniès</name></author><author><name sortKey="Laurent Puig, P" uniqKey="Laurent Puig P">P Laurent-Puig</name></author><author><name sortKey="Zucman Rossi, J" uniqKey="Zucman Rossi J">J Zucman-Rossi</name></author><author><name sortKey="Dieu Nosjean, M C" uniqKey="Dieu Nosjean M">M-C Dieu-Nosjean</name></author><author><name sortKey="Sautes Fridman, C" uniqKey="Sautes Fridman C">C Sautès-Fridman</name></author><author><name sortKey="Fridman, Wh" uniqKey="Fridman W">WH Fridman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kandoth, C" uniqKey="Kandoth C">C Kandoth</name></author><author><name sortKey="Schultz, N" uniqKey="Schultz N">N Schultz</name></author><author><name sortKey="Cherniack, Ad" uniqKey="Cherniack A">AD Cherniack</name></author><author><name sortKey="Akbani, R" uniqKey="Akbani R">R Akbani</name></author><author><name sortKey="Liu, Y" uniqKey="Liu Y">Y Liu</name></author><author><name sortKey="Shen, H" uniqKey="Shen H">H Shen</name></author><author><name sortKey="Robertson, Ag" uniqKey="Robertson A">AG Robertson</name></author><author><name sortKey="Pashtan, I" uniqKey="Pashtan I">I Pashtan</name></author><author><name sortKey="Shen, R" uniqKey="Shen R">R Shen</name></author><author><name sortKey="Benz, Cc" uniqKey="Benz C">CC Benz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Gool, Ic" uniqKey="Van Gool I">IC van Gool</name></author><author><name sortKey="Eggink, Fa" uniqKey="Eggink F">FA Eggink</name></author><author><name sortKey="Freeman Mills, L" uniqKey="Freeman Mills L">L Freeman-Mills</name></author><author><name sortKey="Stelloo, E" uniqKey="Stelloo E">E Stelloo</name></author><author><name sortKey="Marchi, E" uniqKey="Marchi E">E Marchi</name></author><author><name sortKey="De Bruyn, M" uniqKey="De Bruyn M">M de Bruyn</name></author><author><name sortKey="Palles, C" uniqKey="Palles C">C Palles</name></author><author><name sortKey="Nout, Ra" uniqKey="Nout R">RA Nout</name></author><author><name sortKey="De Kroon, Cd" uniqKey="De Kroon C">CD de Kroon</name></author><author><name sortKey="Osse, Em" uniqKey="Osse E">EM Osse</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Howitt, Be" uniqKey="Howitt B">BE Howitt</name></author><author><name sortKey="Shukla, Sa" uniqKey="Shukla S">SA Shukla</name></author><author><name sortKey="Sholl, Lm" uniqKey="Sholl L">LM Sholl</name></author><author><name sortKey="Ritterhouse, Ll" uniqKey="Ritterhouse L">LL Ritterhouse</name></author><author><name sortKey="Watkins, Jc" uniqKey="Watkins J">JC Watkins</name></author><author><name sortKey="Rodig, S" uniqKey="Rodig S">S Rodig</name></author><author><name sortKey="Stover, E" uniqKey="Stover E">E Stover</name></author><author><name sortKey="Strickland, Kc" uniqKey="Strickland K">KC Strickland</name></author><author><name sortKey="D Andrea, Ad" uniqKey="D Andrea A">AD D'Andrea</name></author><author><name sortKey="Wu, Cj" uniqKey="Wu C">CJ Wu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bellone, S" uniqKey="Bellone S">S Bellone</name></author><author><name sortKey="Centritto, F" uniqKey="Centritto F">F Centritto</name></author><author><name sortKey="Black, J" uniqKey="Black J">J Black</name></author><author><name sortKey="Schwab, C" uniqKey="Schwab C">C Schwab</name></author><author><name sortKey="English, D" uniqKey="English D">D English</name></author><author><name sortKey="Cocco, E" uniqKey="Cocco E">E Cocco</name></author><author><name sortKey="Lopez, S" uniqKey="Lopez S">S Lopez</name></author><author><name sortKey="Bonazzoli, E" uniqKey="Bonazzoli E">E Bonazzoli</name></author><author><name sortKey="Predolini, F" uniqKey="Predolini F">F Predolini</name></author><author><name sortKey="Ferrari, F" uniqKey="Ferrari F">F Ferrari</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Gool, Ic" uniqKey="Van Gool I">IC van Gool</name></author><author><name sortKey="Bosse, T" uniqKey="Bosse T">T Bosse</name></author><author><name sortKey="Church, Dn" uniqKey="Church D">DN Church</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gros, A" uniqKey="Gros A">A Gros</name></author><author><name sortKey="Parkhurst, Mr" uniqKey="Parkhurst M">MR Parkhurst</name></author><author><name sortKey="Tran, E" uniqKey="Tran E">E Tran</name></author><author><name sortKey="Pasetto, A" uniqKey="Pasetto A">A Pasetto</name></author><author><name sortKey="Robbins, Pf" uniqKey="Robbins P">PF Robbins</name></author><author><name sortKey="Ilyas, S" uniqKey="Ilyas S">S Ilyas</name></author><author><name sortKey="Prickett, Td" uniqKey="Prickett T">TD Prickett</name></author><author><name sortKey="Gartner, Jj" uniqKey="Gartner J">JJ Gartner</name></author><author><name sortKey="Crystal, Js" uniqKey="Crystal J">JS Crystal</name></author><author><name sortKey="Roberts, Im" uniqKey="Roberts I">IM Roberts</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mehnert, Jm" uniqKey="Mehnert J">JM Mehnert</name></author><author><name sortKey="Panda, A" uniqKey="Panda A">A Panda</name></author><author><name sortKey="Zhong, H" uniqKey="Zhong H">H Zhong</name></author><author><name sortKey="Hirshfield, K" uniqKey="Hirshfield K">K Hirshfield</name></author><author><name sortKey="Damare, S" uniqKey="Damare S">S Damare</name></author><author><name sortKey="Lane, K" uniqKey="Lane K">K Lane</name></author><author><name sortKey="Sokol, L" uniqKey="Sokol L">L Sokol</name></author><author><name sortKey="Stein, Mn" uniqKey="Stein M">MN Stein</name></author><author><name sortKey="Rodriguez Rodriquez, L" uniqKey="Rodriguez Rodriquez L">L Rodriguez-rodriquez</name></author><author><name sortKey="Kaufman, Hl" uniqKey="Kaufman H">HL Kaufman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Santin, Ad" uniqKey="Santin A">AD Santin</name></author><author><name sortKey="Bellone, S" uniqKey="Bellone S">S Bellone</name></author><author><name sortKey="Buza, N" uniqKey="Buza N">N Buza</name></author><author><name sortKey="Choi, J" uniqKey="Choi J">J Choi</name></author><author><name sortKey="Schwartz, Pe" uniqKey="Schwartz P">PE Schwartz</name></author><author><name sortKey="Schlessinger, J" uniqKey="Schlessinger J">J Schlessinger</name></author><author><name sortKey="Lifton, Rp" uniqKey="Lifton R">RP Lifton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dong, H" uniqKey="Dong H">H Dong</name></author><author><name sortKey="Strome, Se" uniqKey="Strome S">SE Strome</name></author><author><name sortKey="Salomao, Dr" uniqKey="Salomao D">DR Salomao</name></author><author><name sortKey="Tamura, H" uniqKey="Tamura H">H Tamura</name></author><author><name sortKey="Hirano, F" uniqKey="Hirano F">F Hirano</name></author><author><name sortKey="Flies, Db" uniqKey="Flies D">DB Flies</name></author><author><name sortKey="Roche, Pc" uniqKey="Roche P">PC Roche</name></author><author><name sortKey="Lu, J" uniqKey="Lu J">J Lu</name></author><author><name sortKey="Zhu, G" uniqKey="Zhu G">G Zhu</name></author><author><name sortKey="Tamada, K" uniqKey="Tamada K">K Tamada</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Heeren, Am" uniqKey="Heeren A">AM Heeren</name></author><author><name sortKey="Koster, Bd" uniqKey="Koster B">BD Koster</name></author><author><name sortKey="Samuels, S" uniqKey="Samuels S">S Samuels</name></author><author><name sortKey="Ferns, Dm" uniqKey="Ferns D">DM Ferns</name></author><author><name sortKey="Chondronasiou, D" uniqKey="Chondronasiou D">D Chondronasiou</name></author><author><name sortKey="Kenter, Gg" uniqKey="Kenter G">GG Kenter</name></author><author><name sortKey="Jordanova, Es" uniqKey="Jordanova E">ES Jordanova</name></author><author><name sortKey="De Gruijl, Td" uniqKey="De Gruijl T">TD de Gruijl</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schultheis, Am" uniqKey="Schultheis A">AM Schultheis</name></author><author><name sortKey="Scheel, Ah" uniqKey="Scheel A">AH Scheel</name></author><author><name sortKey="Ozreti, L" uniqKey="Ozreti L">L Ozretić</name></author><author><name sortKey="George, J" uniqKey="George J">J George</name></author><author><name sortKey="Thomas, Rk" uniqKey="Thomas R">RK Thomas</name></author><author><name sortKey="Hagemann, T" uniqKey="Hagemann T">T Hagemann</name></author><author><name sortKey="Zander, T" uniqKey="Zander T">T Zander</name></author><author><name sortKey="Wolf, J" uniqKey="Wolf J">J Wolf</name></author><author><name sortKey="Buettner, R" uniqKey="Buettner R">R Buettner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Curiel, Tj" uniqKey="Curiel T">TJ Curiel</name></author><author><name sortKey="Wei, S" uniqKey="Wei S">S Wei</name></author><author><name sortKey="Dong, H" uniqKey="Dong H">H Dong</name></author><author><name sortKey="Alvarez, X" uniqKey="Alvarez X">X Alvarez</name></author><author><name sortKey="Cheng, P" uniqKey="Cheng P">P Cheng</name></author><author><name sortKey="Mottram, P" uniqKey="Mottram P">P Mottram</name></author><author><name sortKey="Krzysiek, R" uniqKey="Krzysiek R">R Krzysiek</name></author><author><name sortKey="Knutson, Kl" uniqKey="Knutson K">KL Knutson</name></author><author><name sortKey="Daniel, B" uniqKey="Daniel B">B Daniel</name></author><author><name sortKey="Zimmermann, Mc" uniqKey="Zimmermann M">MC Zimmermann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bakhsh, S" uniqKey="Bakhsh S">S Bakhsh</name></author><author><name sortKey="Kinloch, M" uniqKey="Kinloch M">M Kinloch</name></author><author><name sortKey="Hoang, Ln" uniqKey="Hoang L">LN Hoang</name></author><author><name sortKey="Soslow, Ra" uniqKey="Soslow R">RA Soslow</name></author><author><name sortKey="Kobel, M" uniqKey="Kobel M">M Köbel</name></author><author><name sortKey="Lee, Ch" uniqKey="Lee C">CH Lee</name></author><author><name sortKey="Mcalpine, Jn" uniqKey="Mcalpine J">JN Mcalpine</name></author><author><name sortKey="Mcconechy, Mk" uniqKey="Mcconechy M">MK Mcconechy</name></author><author><name sortKey="Gilks, Cb" uniqKey="Gilks C">CB Gilks</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mclaughlin, J" uniqKey="Mclaughlin J">J McLaughlin</name></author><author><name sortKey="Han, G" uniqKey="Han G">G Han</name></author><author><name sortKey="Schalper, Ka" uniqKey="Schalper K">KA Schalper</name></author><author><name sortKey="Carvajal Hausdorf, D" uniqKey="Carvajal Hausdorf D">D Carvajal-Hausdorf</name></author><author><name sortKey="Pelekanou, V" uniqKey="Pelekanou V">V Pelekanou</name></author><author><name sortKey="Rehman, J" uniqKey="Rehman J">J Rehman</name></author><author><name sortKey="Velcheti, V" uniqKey="Velcheti V">V Velcheti</name></author><author><name sortKey="Herbst, R" uniqKey="Herbst R">R Herbst</name></author><author><name sortKey="Lorusso, P" uniqKey="Lorusso P">P LoRusso</name></author><author><name sortKey="Rimm, Dl" uniqKey="Rimm D">DL Rimm</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dieu Nosjean, Mc" uniqKey="Dieu Nosjean M">MC Dieu-Nosjean</name></author><author><name sortKey="Giraldo, Na" uniqKey="Giraldo N">NA Giraldo</name></author><author><name sortKey="Kaplon, H" uniqKey="Kaplon H">H Kaplon</name></author><author><name sortKey="Germain, C" uniqKey="Germain C">C Germain</name></author><author><name sortKey="Fridman, Wh" uniqKey="Fridman W">WH Fridman</name></author><author><name sortKey="Sautes Fridman, C" uniqKey="Sautes Fridman C">C Sautès-Fridman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Germain, C" uniqKey="Germain C">C Germain</name></author><author><name sortKey="Gnjatic, S" uniqKey="Gnjatic S">S Gnjatic</name></author><author><name sortKey="Dieu Nosjean, Mc" uniqKey="Dieu Nosjean M">MC Dieu-Nosjean</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kroeger, Dr" uniqKey="Kroeger D">DR Kroeger</name></author><author><name sortKey="Milne, K" uniqKey="Milne K">K Milne</name></author><author><name sortKey="Nelson, Bh" uniqKey="Nelson B">BH Nelson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, H" uniqKey="Zhang H">H Zhang</name></author><author><name sortKey="Liu, T" uniqKey="Liu T">T Liu</name></author><author><name sortKey="Zhang, Z" uniqKey="Zhang Z">Z Zhang</name></author><author><name sortKey="Chan, Dw" uniqKey="Chan D">DW Chan</name></author><author><name sortKey="Rodland, Kd" uniqKey="Rodland K">KD Rodland</name></author><author><name sortKey="Zhang, H" uniqKey="Zhang H">H Zhang</name></author><author><name sortKey="Liu, T" uniqKey="Liu T">T Liu</name></author><author><name sortKey="Zhang, Z" uniqKey="Zhang Z">Z Zhang</name></author><author><name sortKey="Payne, Sh" uniqKey="Payne S">SH Payne</name></author><author><name sortKey="Zhang, B" uniqKey="Zhang B">B Zhang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stelloo, E" uniqKey="Stelloo E">E Stelloo</name></author><author><name sortKey="Versluis, Ma" uniqKey="Versluis M">MA Versluis</name></author><author><name sortKey="Nijman, Hw" uniqKey="Nijman H">HW Nijman</name></author><author><name sortKey="De Bruyn, M" uniqKey="De Bruyn M">M de Bruyn</name></author><author><name sortKey="Plat, A" uniqKey="Plat A">A Plat</name></author><author><name sortKey="Osse, Em" uniqKey="Osse E">EM Osse</name></author><author><name sortKey="Van Dijk, Rh" uniqKey="Van Dijk R">RH van Dijk</name></author><author><name sortKey="Nout, Ra" uniqKey="Nout R">RA Nout</name></author><author><name sortKey="Creutzberg, Cl" uniqKey="Creutzberg C">CL Creutzberg</name></author><author><name sortKey="De Bock, Gh" uniqKey="De Bock G">GH de Bock</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Taube, Jm" uniqKey="Taube J">JM Taube</name></author><author><name sortKey="Klein, A" uniqKey="Klein A">A Klein</name></author><author><name sortKey="Brahmer, Jr" uniqKey="Brahmer J">JR Brahmer</name></author><author><name sortKey="Xu, H" uniqKey="Xu H">H Xu</name></author><author><name sortKey="Pan, X" uniqKey="Pan X">X Pan</name></author><author><name sortKey="Kim, Jh" uniqKey="Kim J">JH Kim</name></author><author><name sortKey="Chen, L" uniqKey="Chen L">L Chen</name></author><author><name sortKey="Pardoll, Dm" uniqKey="Pardoll D">DM Pardoll</name></author><author><name sortKey="Topalian, Sl" uniqKey="Topalian S">SL Topalian</name></author><author><name sortKey="Anders, Ra" uniqKey="Anders R">RA Anders</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Billingsley, Cc" uniqKey="Billingsley C">CC Billingsley</name></author><author><name sortKey="Cohn, De" uniqKey="Cohn D">DE Cohn</name></author><author><name sortKey="Mutch, Dg" uniqKey="Mutch D">DG Mutch</name></author><author><name sortKey="Hade, Em" uniqKey="Hade E">EM Hade</name></author><author><name sortKey="Goodfellow, Pj" uniqKey="Goodfellow P">PJ Goodfellow</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Church, Dn" uniqKey="Church D">DN Church</name></author><author><name sortKey="Stelloo, E" uniqKey="Stelloo E">E Stelloo</name></author><author><name sortKey="Nout, Ra" uniqKey="Nout R">RA Nout</name></author><author><name sortKey="Valtcheva, N" uniqKey="Valtcheva N">N Valtcheva</name></author><author><name sortKey="Depreeuw, J" uniqKey="Depreeuw J">J Depreeuw</name></author><author><name sortKey="Ter Haar, N" uniqKey="Ter Haar N">N ter Haar</name></author><author><name sortKey="Noske, A" uniqKey="Noske A">A Noske</name></author><author><name sortKey="Amant, F" uniqKey="Amant F">F Amant</name></author><author><name sortKey="Tomlinson, Ip" uniqKey="Tomlinson I">IP Tomlinson</name></author><author><name sortKey="Wild, Pj" uniqKey="Wild P">PJ Wild</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mcconechy, Mk" uniqKey="Mcconechy M">MK McConechy</name></author><author><name sortKey="Talhouk, A" uniqKey="Talhouk A">A Talhouk</name></author><author><name sortKey="Leung, S" uniqKey="Leung S">S Leung</name></author><author><name sortKey="Chiu, D" uniqKey="Chiu D">D Chiu</name></author><author><name sortKey="Yang, W" uniqKey="Yang W">W Yang</name></author><author><name sortKey="Senz, J" uniqKey="Senz J">J Senz</name></author><author><name sortKey="Reha Krantz, Lj" uniqKey="Reha Krantz L">LJ Reha-Krantz</name></author><author><name sortKey="Lee, C H" uniqKey="Lee C">C-H Lee</name></author><author><name sortKey="Huntsman, Dg" uniqKey="Huntsman D">DG Huntsman</name></author><author><name sortKey="Gilks, Cb" uniqKey="Gilks C">CB Gilks</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stelloo, E" uniqKey="Stelloo E">E Stelloo</name></author><author><name sortKey="Bosse, T" uniqKey="Bosse T">T Bosse</name></author><author><name sortKey="Nout, Ra" uniqKey="Nout R">RA Nout</name></author><author><name sortKey="Mackay, Hj" uniqKey="Mackay H">HJ MacKay</name></author><author><name sortKey="Church, Dn" uniqKey="Church D">DN Church</name></author><author><name sortKey="Nijman, Hw" uniqKey="Nijman H">HW Nijman</name></author><author><name sortKey="Leary, A" uniqKey="Leary A">A Leary</name></author><author><name sortKey="Edmondson, Rj" uniqKey="Edmondson R">RJ Edmondson</name></author><author><name sortKey="Powell, Me" uniqKey="Powell M">ME Powell</name></author><author><name sortKey="Crosbie, Ej" uniqKey="Crosbie E">EJ Crosbie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Church, Dn" uniqKey="Church D">DN Church</name></author><author><name sortKey="Briggs, Sew" uniqKey="Briggs S">SEW Briggs</name></author><author><name sortKey="Palles, C" uniqKey="Palles C">C Palles</name></author><author><name sortKey="Domingo, E" uniqKey="Domingo E">E Domingo</name></author><author><name sortKey="Kearsey, Sj" uniqKey="Kearsey S">SJ Kearsey</name></author><author><name sortKey="Grimes, Jm" uniqKey="Grimes J">JM Grimes</name></author><author><name sortKey="Gorman, M" uniqKey="Gorman M">M Gorman</name></author><author><name sortKey="Martin, L" uniqKey="Martin L">L Martin</name></author><author><name sortKey="Howarth, Km" uniqKey="Howarth K">KM Howarth</name></author><author><name sortKey="Hodgson, S V" uniqKey="Hodgson S">S V Hodgson</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Alexandrov, Lb" uniqKey="Alexandrov L">LB Alexandrov</name></author><author><name sortKey="Nik Zainal, S" uniqKey="Nik Zainal S">S Nik-Zainal</name></author><author><name sortKey="Wedge, Dc" uniqKey="Wedge D">DC Wedge</name></author><author><name sortKey="Aparicio, Sa" uniqKey="Aparicio S">SA Aparicio</name></author><author><name sortKey="Behjati, S" uniqKey="Behjati S">S Behjati</name></author><author><name sortKey="Biankin, A V" uniqKey="Biankin A">A V Biankin</name></author><author><name sortKey="Bignell, Gr" uniqKey="Bignell G">GR Bignell</name></author><author><name sortKey="Bolli, N" uniqKey="Bolli N">N Bolli</name></author><author><name sortKey="Borg, A" uniqKey="Borg A">A Borg</name></author><author><name sortKey="B Rresen Dale, A L" uniqKey="B Rresen Dale A">A-L Børresen-Dale</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shinbrot, E" uniqKey="Shinbrot E">E Shinbrot</name></author><author><name sortKey="Henninger, Ee" uniqKey="Henninger E">EE Henninger</name></author><author><name sortKey="Weinhold, N" uniqKey="Weinhold N">N Weinhold</name></author><author><name sortKey="Covington, Kr" uniqKey="Covington K">KR Covington</name></author><author><name sortKey="Goksenin, Ay" uniqKey="Goksenin A">AY Göksenin</name></author><author><name sortKey="Schultz, N" uniqKey="Schultz N">N Schultz</name></author><author><name sortKey="Chao, H" uniqKey="Chao H">H Chao</name></author><author><name sortKey="Doddapaneni, H" uniqKey="Doddapaneni H">H Doddapaneni</name></author><author><name sortKey="Muzny, Dm" uniqKey="Muzny D">DM Muzny</name></author><author><name sortKey="Gibbs, Ra" uniqKey="Gibbs R">RA Gibbs</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Erson Omay, Ez" uniqKey="Erson Omay E">EZ Erson-Omay</name></author><author><name sortKey="Ca Layan, Ao" uniqKey="Ca Layan A">AO Çağlayan</name></author><author><name sortKey="Schultz, N" uniqKey="Schultz N">N Schultz</name></author><author><name sortKey="Weinhold, N" uniqKey="Weinhold N">N Weinhold</name></author><author><name sortKey="Omay, Sb" uniqKey="Omay S">SB Omay</name></author><author><name sortKey="Ozduman, K" uniqKey="Ozduman K">K Özduman</name></author><author><name sortKey="Koksal, Y" uniqKey="Koksal Y">Y Köksal</name></author><author><name sortKey="Li, J" uniqKey="Li J">J Li</name></author><author><name sortKey="Serin Harmanc, A" uniqKey="Serin Harmanc A">A Serin Harmancı</name></author><author><name sortKey="Clark, V" uniqKey="Clark V">V Clark</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rayner, E" uniqKey="Rayner E">E Rayner</name></author><author><name sortKey="Van Gool, Ic" uniqKey="Van Gool I">IC van Gool</name></author><author><name sortKey="Palles, C" uniqKey="Palles C">C Palles</name></author><author><name sortKey="Kearsey, Se" uniqKey="Kearsey S">SE Kearsey</name></author><author><name sortKey="Bosse, T" uniqKey="Bosse T">T Bosse</name></author><author><name sortKey="Tomlinson, I" uniqKey="Tomlinson I">I Tomlinson</name></author><author><name sortKey="Church, Dn" uniqKey="Church D">DN Church</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Domingo, E" uniqKey="Domingo E">E Domingo</name></author><author><name sortKey="Freeman Mills, L" uniqKey="Freeman Mills L">L Freeman-Mills</name></author><author><name sortKey="Rayner, E" uniqKey="Rayner E">E Rayner</name></author><author><name sortKey="Glaire, M" uniqKey="Glaire M">M Glaire</name></author><author><name sortKey="Briggs, S" uniqKey="Briggs S">S Briggs</name></author><author><name sortKey="Vermeulen, L" uniqKey="Vermeulen L">L Vermeulen</name></author><author><name sortKey="Fessler, E" uniqKey="Fessler E">E Fessler</name></author><author><name sortKey="Medema, Jp" uniqKey="Medema J">JP Medema</name></author><author><name sortKey="Boot, A" uniqKey="Boot A">A Boot</name></author><author><name sortKey="Morreau, H" uniqKey="Morreau H">H Morreau</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gargiulo, P" uniqKey="Gargiulo P">P Gargiulo</name></author><author><name sortKey="Della Pepa, C" uniqKey="Della Pepa C">C Della Pepa</name></author><author><name sortKey="Berardi, S" uniqKey="Berardi S">S Berardi</name></author><author><name sortKey="Califano, D" uniqKey="Califano D">D Califano</name></author><author><name sortKey="Scala, S" uniqKey="Scala S">S Scala</name></author><author><name sortKey="Buonaguro, L" uniqKey="Buonaguro L">L Buonaguro</name></author><author><name sortKey="Ciliberto, G" uniqKey="Ciliberto G">G Ciliberto</name></author><author><name sortKey="Brauchli, P" uniqKey="Brauchli P">P Brauchli</name></author><author><name sortKey="Pignata, S" uniqKey="Pignata S">S Pignata</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Boer, Sm" uniqKey="De Boer S">SM De Boer</name></author><author><name sortKey="Powell, Me" uniqKey="Powell M">ME Powell</name></author><author><name sortKey="Mileshkin, L" uniqKey="Mileshkin L">L Mileshkin</name></author><author><name sortKey="Katsaros, D" uniqKey="Katsaros D">D Katsaros</name></author><author><name sortKey="Bessette, P" uniqKey="Bessette P">P Bessette</name></author><author><name sortKey="Haie Meder, C" uniqKey="Haie Meder C">C Haie-meder</name></author><author><name sortKey="Ottevanger, Pb" uniqKey="Ottevanger P">PB Ottevanger</name></author><author><name sortKey="Ledermann, Ja" uniqKey="Ledermann J">JA Ledermann</name></author><author><name sortKey="Khaw, P" uniqKey="Khaw P">P Khaw</name></author><author><name sortKey="Colombo, A" uniqKey="Colombo A">A Colombo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Eijk, R" uniqKey="Van Eijk R">R van Eijk</name></author><author><name sortKey="Stevens, L" uniqKey="Stevens L">L Stevens</name></author><author><name sortKey="Morreau, H" uniqKey="Morreau H">H Morreau</name></author><author><name sortKey="Van Wezel, T" uniqKey="Van Wezel T">T van Wezel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Gool, Ic" uniqKey="Van Gool I">IC Van Gool</name></author><author><name sortKey="Stelloo, E" uniqKey="Stelloo E">E Stelloo</name></author><author><name sortKey="Nout, Ra" uniqKey="Nout R">RA Nout</name></author><author><name sortKey="Nijman, Hw" uniqKey="Nijman H">HW Nijman</name></author><author><name sortKey="Edmondson, Rj" uniqKey="Edmondson R">RJ Edmondson</name></author><author><name sortKey="Church, Dn" uniqKey="Church D">DN Church</name></author><author><name sortKey="Mackay, Hj" uniqKey="Mackay H">HJ MacKay</name></author><author><name sortKey="Leary, A" uniqKey="Leary A">A Leary</name></author><author><name sortKey="Powell, Me" uniqKey="Powell M">ME Powell</name></author><author><name sortKey="Mileshkin, L" uniqKey="Mileshkin L">L Mileshkin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Workel, Hh" uniqKey="Workel H">HH Workel</name></author><author><name sortKey="Komdeur, Fl" uniqKey="Komdeur F">FL Komdeur</name></author><author><name sortKey="Wouters, Mca" uniqKey="Wouters M">MCA Wouters</name></author><author><name sortKey="Plat, A" uniqKey="Plat A">A Plat</name></author><author><name sortKey="Klip, Hg" uniqKey="Klip H">HG Klip</name></author><author><name sortKey="Eggink, Fa" uniqKey="Eggink F">FA Eggink</name></author><author><name sortKey="Wisman, Gba" uniqKey="Wisman G">GBA Wisman</name></author><author><name sortKey="Arts, Hjg" uniqKey="Arts H">HJG Arts</name></author><author><name sortKey="Oonk, Mhm" uniqKey="Oonk M">MHM Oonk</name></author><author><name sortKey="Mourits, Mje" uniqKey="Mourits M">MJE Mourits</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jordanova, Es" uniqKey="Jordanova E">ES Jordanova</name></author><author><name sortKey="Gorter, A" uniqKey="Gorter A">A Gorter</name></author><author><name sortKey="Ayachi, O" uniqKey="Ayachi O">O Ayachi</name></author><author><name sortKey="Prins, F" uniqKey="Prins F">F Prins</name></author><author><name sortKey="Durrant, Lg" uniqKey="Durrant L">LG Durrant</name></author><author><name sortKey="Kenter, Gg" uniqKey="Kenter G">GG Kenter</name></author><author><name sortKey="Van Der Burg, Sh" uniqKey="Van Der Burg S">SH van der Burg</name></author><author><name sortKey="Fleuren, Gj" uniqKey="Fleuren G">GJ Fleuren</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nielsen, M" uniqKey="Nielsen M">M Nielsen</name></author><author><name sortKey="Lundegaard, C" uniqKey="Lundegaard C">C Lundegaard</name></author><author><name sortKey="Blicher, T" uniqKey="Blicher T">T Blicher</name></author><author><name sortKey="Lamberth, K" uniqKey="Lamberth K">K Lamberth</name></author><author><name sortKey="Harndahl, M" uniqKey="Harndahl M">M Harndahl</name></author><author><name sortKey="Justesen, S" uniqKey="Justesen S">S Justesen</name></author><author><name sortKey="R Der, G" uniqKey="R Der G">G Røder</name></author><author><name sortKey="Peters, B" uniqKey="Peters B">B Peters</name></author><author><name sortKey="Sette, A" uniqKey="Sette A">A Sette</name></author><author><name sortKey="Lund, O" uniqKey="Lund O">O Lund</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Khalili, Js" uniqKey="Khalili J">JS Khalili</name></author><author><name sortKey="Hanson, Rw" uniqKey="Hanson R">RW Hanson</name></author><author><name sortKey="Szallasi, Z" uniqKey="Szallasi Z">Z Szallasi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Duan, F" uniqKey="Duan F">F Duan</name></author><author><name sortKey="Duitama, J" uniqKey="Duitama J">J Duitama</name></author><author><name sortKey="Al Seesi, S" uniqKey="Al Seesi S">S Al Seesi</name></author><author><name sortKey="Ayres, Cm" uniqKey="Ayres C">CM Ayres</name></author><author><name sortKey="Corcelli, Sa" uniqKey="Corcelli S">SA Corcelli</name></author><author><name sortKey="Pawashe, Ap" uniqKey="Pawashe A">AP Pawashe</name></author><author><name sortKey="Blanchard, T" uniqKey="Blanchard T">T Blanchard</name></author><author><name sortKey="Mcmahon, D" uniqKey="Mcmahon D">D McMahon</name></author><author><name sortKey="Sidney, J" uniqKey="Sidney J">J Sidney</name></author><author><name sortKey="Sette, A" uniqKey="Sette A">A Sette</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Rooij, N" uniqKey="Van Rooij N">N van Rooij</name></author><author><name sortKey="Van Buuren, Mm" uniqKey="Van Buuren M">MM van Buuren</name></author><author><name sortKey="Philips, D" uniqKey="Philips D">D Philips</name></author><author><name sortKey="Velds, A" uniqKey="Velds A">A Velds</name></author><author><name sortKey="Toebes, M" uniqKey="Toebes M">M Toebes</name></author><author><name sortKey="Heemskerk, B" uniqKey="Heemskerk B">B Heemskerk</name></author><author><name sortKey="Van Dijk, Lja" uniqKey="Van Dijk L">LJA van Dijk</name></author><author><name sortKey="Behjati, S" uniqKey="Behjati S">S Behjati</name></author><author><name sortKey="Hilkmann, H" uniqKey="Hilkmann H">H Hilkmann</name></author><author><name sortKey="El Atmioui, D" uniqKey="El Atmioui D">D El Atmioui</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Oncoimmunology</journal-id><journal-id journal-id-type="iso-abbrev">Oncoimmunology</journal-id><journal-id journal-id-type="publisher-id">KONI</journal-id><journal-id journal-id-type="publisher-id">koni20</journal-id><journal-title-group><journal-title>Oncoimmunology</journal-title></journal-title-group><issn pub-type="ppub">2162-4011</issn><issn pub-type="epub">2162-402X</issn><publisher><publisher-name>Taylor & Francis</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28344870</article-id><article-id pub-id-type="pmc">5353925</article-id><article-id pub-id-type="publisher-id">1264565</article-id><article-id pub-id-type="doi">10.1080/2162402X.2016.1264565</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Research</subject></subj-group></article-categories><title-group><article-title>Immunological profiling of molecularly classified high-risk endometrial cancers identifies <italic>POLE</italic>-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition</article-title><alt-title alt-title-type="running-authors">F. A. EGGINK ET AL.</alt-title><alt-title alt-title-type="running-title">ONCOIMMUNOLOGY</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Eggink</surname><given-names>Florine A.</given-names></name><xref ref-type="aff" rid="af0001"><sup>a</sup></xref><xref ref-type="author-notes" rid="afn0001"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Van Gool</surname><given-names>Inge C.</given-names></name><xref ref-type="aff" rid="af0002"><sup>b</sup></xref><xref ref-type="author-notes" rid="afn0001"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Leary</surname><given-names>Alexandra</given-names></name><xref ref-type="aff" rid="af0003"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pollock</surname><given-names>Pamela M.</given-names></name><xref ref-type="aff" rid="af0004"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Crosbie</surname><given-names>Emma J.</given-names></name><xref ref-type="aff" rid="af0005"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mileshkin</surname><given-names>Linda</given-names></name><xref ref-type="aff" rid="af0006"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jordanova</surname><given-names>Ekaterina S.</given-names></name><xref ref-type="aff" rid="af0002"><sup>b</sup></xref><xref ref-type="aff" rid="af0007"><sup>g</sup></xref></contrib><contrib contrib-type="author"><name><surname>Adam</surname><given-names>Julien</given-names></name><xref ref-type="aff" rid="af0003"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Freeman-Mills</surname><given-names>Luke</given-names></name><xref ref-type="aff" rid="af0008"><sup>h</sup></xref></contrib><contrib contrib-type="author"><name><surname>Church</surname><given-names>David N.</given-names></name><xref ref-type="aff" rid="af0008"><sup>h</sup></xref><xref ref-type="aff" rid="af0009"><sup>i</sup></xref></contrib><contrib contrib-type="author"><name><surname>Creutzberg</surname><given-names>Carien L.</given-names></name><xref ref-type="aff" rid="af0010"><sup>j</sup></xref></contrib><contrib contrib-type="author"><name><surname>De Bruyn</surname><given-names>Marco</given-names></name><xref ref-type="aff" rid="af0001"><sup>a</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="ORCID">0000-0002-1821-3042</contrib-id><name><surname>Nijman</surname><given-names>Hans W.</given-names></name><xref ref-type="aff" rid="af0001"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bosse</surname><given-names>Tjalling</given-names></name><xref ref-type="aff" rid="af0002"><sup>b</sup></xref><xref ref-type="corresp" rid="an0001"></xref></contrib><aff id="af0001"><label>a</label><institution>Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen</institution>, Groningen,<country>the Netherlands</country></aff><aff id="af0002"><label>b</label><institution>Department of Pathology, Leiden University Medical Center</institution>, Leiden,<country>the Netherlands</country></aff><aff id="af0003"><label>c</label><institution>Department of Medical Oncology, INSERM U981, Gustave Roussy Cancer Center</institution>, Villejuif,<country>France</country></aff><aff id="af0004"><label>d</label><institution>Queensland University of Technology (QUT), Translational Research Institute</institution>, Brisbane, QLD,<country>Australia</country></aff><aff id="af0005"><label>e</label><institution>Institute of Cancer Sciences, University of Manchester, St Marys Hospital</institution>, Manchester,<country>UK</country></aff><aff id="af0006"><label>f</label><institution>Division of Cancer Medicine, Peter MacCallum Cancer Centre</institution>, East Melbourne, VIC,<country>Australia</country></aff><aff id="af0007"><label>g</label><institution>Center for Gynecological Oncology Amsterdam, VU Medical Center</institution>, Amsterdam,<country>the Netherlands</country></aff><aff id="af0008"><label>h</label><institution>Tumour Genomics and Immunology Group, Oxford Centre for Cancer Gene Research, The Wellcome Trust Centre for Human Genetics, University of Oxford</institution>, Oxford,<country>UK</country></aff><aff id="af0009"><label>i</label><institution>Oxford Cancer Centre, Churchill Hospital</institution>, Oxford,<country>UK</country></aff><aff id="af0010"><label>j</label><institution>Department of Clinical Oncology, Leiden University Medical Center</institution>, Leiden,<country>the Netherlands</country></aff></contrib-group><author-notes><corresp id="an0001"><bold>CONTACT</bold> Tjalling Bosse <email xlink:href="T.Bosse@lumc.nl">T.Bosse@lumc.nl</email><institution>Department of Pathology, Leiden University Medical Center</institution>, <addr-line>PO Box 9600</addr-line>, 2300 RC Leiden, <country>the Netherlands</country></corresp><fn><p>Supplemental data for this article can be accessed on the <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1080/2162402X.2016.1264565">publisher's website</ext-link>.</p></fn><fn id="afn0001"><label>*</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="collection"><year>2017</year></pub-date><pub-date pub-type="epub"><day>9</day><month>12</month><year>2016</year></pub-date><pub-date pub-type="pmc-release"><day>9</day><month>12</month><year>2016</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>6</volume><issue>2</issue><elocation-id seq="10">e1264565</elocation-id><history><date date-type="received"><day>12</day><month>10</month><year>2016</year></date><date date-type="rev-recd"><day>16</day><month>11</month><year>2016</year></date><date date-type="accepted"><day>17</day><month>11</month><year>2016</year></date></history><permissions><pmc-comment> © Florine A. Eggink, Inge C. Van Gool, Alexandra Leary, Pamela M. Pollock, Emma J. Crosbie, Linda Mileshkin, Ekaterina S. Jordanova, Julien Adam, Luke Freeman-Mills, David N. Church, Carien L. Creutzberg, Marco De Bruyn, Hans W. Nijman, and Tjalling Bosse </pmc-comment>
<copyright-statement>© 2017 The Author(s). Published with license by Taylor & Francis Group, LLC</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>The Author(s)</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="koni-06-02-1264565.pdf"></self-uri><abstract><title>ABSTRACT</title><p>High-risk endometrial cancer (EC) is an aggressive disease for which new therapeutic options are needed. Aims of this study were to validate the enhanced immune response in highly mutated ECs and to explore immune profiles in other EC subgroups. We evaluated immune infiltration in 116 high-risk ECs from the TransPORTEC consortium, previously classified into four molecular subtypes: (i) ultramutated <italic>POLE</italic> exonuclease domain-mutant ECs (<italic>POLE</italic>-mutant); (ii) hypermutated microsatellite unstable (MSI); (iii) p53-mutant; and (iv) no specific molecular profile (NSMP). Within The Cancer Genome Atlas (TCGA) EC cohort, significantly higher numbers of predicted neoantigens were demonstrated in <italic>POLE</italic>-mutant and MSI tumors compared with NSMP and p53-mutants. This was reflected by enhanced immune expression and infiltration in <italic>POLE</italic>-mutant and MSI tumors in both the TCGA cohort (mRNA expression) and the TransPORTEC cohort (immunohistochemistry) with high infiltration of CD8<sup>+</sup> (90% and 69%), PD-1<sup>+</sup> (73% and 69%) and PD-L1<sup>+</sup> immune cells (100% and 71%). Notably, a subset of p53-mutant and NSMP cancers was characterized by signs of an antitumor immune response (43% and 31% of tumors with high infiltration of CD8<sup>+</sup> cells, respectively), despite a low number of predicted neoantigens. In conclusion, the presence of enhanced immune infiltration, particularly high numbers of PD-1 and PD-L1 positive cells, in highly mutated, neoantigen-rich <italic>POLE</italic>-mutant and MSI endometrial tumors suggests sensitivity to immune checkpoint inhibitors.</p></abstract><kwd-group kwd-group-type="author"><title>KEYWORDS</title><kwd>Checkpoint inhibition</kwd><kwd>endometrial cancer</kwd><kwd>high-risk</kwd><kwd>molecular classification</kwd><kwd>tumor-infiltrating lymphocytes</kwd></kwd-group><counts><fig-count count="6"></fig-count><table-count count="1"></table-count><equation-count count="0"></equation-count><ref-count count="59"></ref-count><page-count count="13"></page-count></counts></article-meta></front><body><sec sec-type="intro" id="s0001"><title>Introduction</title><p>The development of novel immunotherapeutic strategies such as checkpoint inhibitors has the potential to transform the field of oncology. So far, durable responses have been established in subsets of patients, for example with metastatic melanoma, non-small cell lung cancer, and mismatch repair-deficient cancers including two patients with endometrial cancer (EC).<xref rid="cit0001" ref-type="bibr"><sup>1-7</sup></xref> Although the clinical efficacy of immune checkpoint inhibitors is evident in a subset of patients, selecting the patients who may benefit from this therapy remains challenging. A key mechanism for the benefit of immune checkpoint inhibition in these cancers is the induction of a strong neoantigen-driven T-cell response against the tumor. Indeed, comprehensive analysis of large genomic datasets such as The Cancer Genome Atlas (TCGA) have provided a clear link between mutational load and activation of the immune system, implicating the involvement of neoantigens in driving cytotoxic T-cell responses in cancer.<xref rid="cit0008" ref-type="bibr"><sup>8-10</sup></xref> Furthermore, several clinical trials have shown a strong association between the presence of high numbers of predicted neoantigens, immune infiltration and response to cancer immunotherapy.<xref rid="cit0011" ref-type="bibr"><sup>11-15</sup></xref> In particular, the presence of CD8<sup>+</sup> cytotoxic T cells and expression of the immune checkpoints PD-1 and PD-L1 have been proposed as important predictors of objective tumor regression.<xref rid="cit0003" ref-type="bibr"><sup>3,16</sup></xref></p><p>Characterization of the immune contexture of individual tumors may provide guidance in selecting appropriate immunotherapy for each individual patient, especially when integrated with an analysis of genomic alterations.<xref rid="cit0010" ref-type="bibr"><sup>10,17,18</sup></xref> A molecular classification has recently been proposed by The Cancer Genome Atlas (TCGA), which identified four genomically distinct EC subgroups: an ultramutated group characterized by somatic mutations in the exonuclease domain of <italic>POLE</italic> (encoding the catalytic subunit of DNA polymerase epsilon), a microsatellite unstable (MSI) hypermutated group with many substitutions as well as insertions and deletions due to mismatch repair deficiency, a copy-number high (serous-like) group with frequent <italic>TP53</italic> mutation and a copy-number low (microsatellite stable (MSS)) group with no specific molecular profile (NSMP).<xref rid="cit0019" ref-type="bibr"><sup>19</sup></xref></p><p>In line with this, we, and others, have recently demonstrated high numbers of predicted immunogenic mutations and enhanced antitumor immune infiltration in ultramutated <italic>POLE</italic>-mutant and, to a lesser extent, in hypermutated microsatellite unstable EC.<xref rid="cit0020" ref-type="bibr"><sup>20-23</sup></xref> These studies combined with the emerging data linking mutational load, immune activation and response to cancer immunotherapy render <italic>POLE</italic>-mutated and MSI cancers plausible candidates for immune checkpoint inhibition.<xref rid="cit0003" ref-type="bibr"><sup>3,10-13,24</sup></xref> This is further underlined by recent case reports demonstrating the efficacy of anti-PD-1 inhibitors in advanced <italic>POLE</italic>-mutant or mismatch repair deficient cancers, including those of endometrial origin.<xref rid="cit0007" ref-type="bibr"><sup>7,25,26</sup></xref></p><p>In this study, we aimed to validate our previous findings of an enhanced immune response in <italic>POLE</italic>-mutant and MSI endometrial cancers in a cohort of high-risk patients. High-risk EC patients are a particularly relevant subgroup, as most have no or only very modest gain from standard local or systemic treatment after surgery. Novel treatment options are therefore urgently needed. The use of a molecularly defined cohort of high-risk endometrial cancer also enabled us to explore the immune profiles of the poorly characterized NMSP and p53-mutant subgroups. With this approach we provide a rationale for the administration of checkpoint inhibition strategies in subsets of <italic>POLE</italic>-mutant and MSI endometrial cancer patients.</p></sec><sec sec-type="results" id="s0002"><title>Results</title><sec id="s0002-0001"><title>Enhanced infiltration of intratumoral CD3<sup>+</sup>, CD8<sup>+</sup> and CD103<sup>+</sup> lymphocytes in <italic>POLE</italic>-mutant and MSI tumors</title><p>We first sought to characterize the lymphocytic infiltrate in the four EC molecular subtypes by immunohistochemical analysis of CD3<sup>+</sup>, CD8<sup>+</sup>, CD103<sup>+</sup> and CD20<sup>+</sup> (<xref ref-type="fig" rid="f0001">Fig. 1A and B</xref>). Compared to NSMP and p53-mutant tumors, both <italic>POLE</italic>-mutant and MSI tumors demonstrated increased density of CD3<sup>+</sup> T-lymphocytes within the tumor center (<italic>POLE</italic> vs NSMP <italic>p</italic> = 0.002, MSI vs NSMP <italic>p</italic> = 0.001, MSI vs p53 <italic>p</italic> = 0.018). Staining for cytotoxic T-lymphocyte marker CD8<sup>+</sup> and the intraepithelial T-lymphocyte marker CD103<sup>+</sup> revealed similarly increased infiltrate in the tumor center (comparison of CD8<sup>+</sup> cells: <italic>POLE</italic> vs NSMP <italic>p</italic> < 0.001; <italic>POLE</italic> vs p53 <italic>p</italic> = 0.021; MSI vs NSMP <italic>p</italic> = 0.016, comparison of CD103<sup>+</sup> cells: <italic>POLE</italic> vs MSI <italic>p</italic> = 0.023; MSI vs NSMP <italic>p</italic> = 0.035; MSI vs p53 <italic>p</italic> = 0.030). Based on a median of 80.5 CD8<sup>+</sup> cells/core in the whole cohort, 90% of <italic>POLE</italic>-mutant, 69% of MSI, 31% of NSMP and 43% of p53-mutant tumors were categorized as highly infiltrated with CD8<sup>+</sup> cells. There was no difference in numbers of CD20<sup>+</sup> B-lymphocytes within the tumor center. A combined analysis in which the two molecular subgroups with a high expected neoantigen load (<italic>POLE</italic>-mutant and MSI) were compared with the two molecular subgroups with lower expected neoantigen load (NSMP and p53-mutant), supported the apparent differences in immune infiltrate between EC subtypes (Fig. S1A).
<fig id="f0001" orientation="portrait" position="float"><label>Figure 1.</label><caption><p>Infiltration of CD3<sup>+</sup>, CD8<sup>+</sup>, CD103<sup>+</sup> and CD27<sup>+</sup> cells in <italic>POLE</italic>-mutant, MSI, NSMP and p53-mutant endometrial cancers. (A) Representative immunohistochemical stainings of CD3<sup>+</sup>, CD8<sup>+</sup>, CD103<sup>+</sup> and CD20<sup>+</sup> cells. (B) Average number of positively stained intratumoral cells for each of the markers in the above panel, counted per core, corrected for the number of cells present. (C) Average number of positively stained cells for each of the markers in the above panel, counted per core within the infiltrative margin, corrected for the number of cells present. The numbers of cases analyzed for each molecular subgroup are listed below the <italic>x</italic>-axis. Boxes represent the interquartile range (IQR), with the upper whisker indicating the 75th percentile and the lower whisker the 25th percentile. The median and mean values are indicated by a horizontal line and cross, respectively. Abbreviations: <italic>POLE, POLE</italic>-mutant; MSI, microsatellite unstable; NSMP, no specific molecular profile; p53, p53-mutant. *<italic>p</italic> < 0.05, **<italic>p</italic> < 0.01, ***<italic>p</italic> < 0.001.</p></caption><graphic specific-use="web-only" content-type="color" xlink:href="koni-06-02-1264565-g001"></graphic></fig></p><p>Within the infiltrative margin, CD3<sup>+</sup>, CD8<sup>+</sup>, CD103<sup>+</sup> or CD20<sup>+</sup> infiltration did not significantly differ between the four molecular subgroups (<xref ref-type="fig" rid="f0001">Fig. 1C</xref>). Combined analysis showed a higher infiltration of CD8<sup>+</sup> and CD103<sup>+</sup> in <italic>POLE</italic>-mutant and MSI (CD8<sup>+</sup><italic>p</italic> = 0.010, CD103 <italic>p</italic> = 0.016, Fig. S1B).</p></sec><sec id="s0002-0002"><title>Increased infiltration of CD45RO<sup>+</sup> and TIA-1<sup>+</sup> lymphocytes in MSI tumors</title><p>To analyze the function of the tumors' lymphocytic infiltrate, we performed immunohistochemistry for CD45RO, CD27, T-Bet and TIA-1 (<xref ref-type="fig" rid="f0002">Fig. 2A and B</xref>). Within the tumor center, MSI tumors contained more CD45RO<sup>+</sup> memory T-lymphocytes compared with NSMP and p53-mutant tumors (MSI vs NSMP <italic>p</italic> = 0.029, MSI vs p53 <italic>p</italic> = 0.008). MSI tumors also harbored more TIA-1<sup>+</sup> cytolytic lymphocytes within the tumor center (MSI vs NSMP <italic>p</italic> = 0.019, MSI vs p53 <italic>p</italic> = 0.043). There were no differences in the numbers of CD27<sup>+</sup> naive T cells and T-Bet<sup>+</sup> differentiated cells between the four molecular subgroups. Combined analysis of molecular groups revealed the presence of more CD45RO<sup>+</sup> and TIA-1<sup>+</sup> cells in <italic>POLE</italic>-mutant/MSI tumors compared with NSMP/p53-mutant tumors (Fig. S2A). Moreover, this also demonstrated higher numbers of T-Bet<sup>+</sup> differentiated cells within <italic>POLE</italic>-mutant/MSI tumors compared with NSMP/p53-mutant tumors (<italic>p</italic> = 0.021).
<fig id="f0002" orientation="portrait" position="float"><label>Figure 2.</label><caption><p>Infiltration of TIA-1<sup>+</sup>, T-Bet<sup>+</sup>, CD20<sup>+</sup> and CD45RO<sup>+</sup> cells in <italic>POLE</italic>-mutant, MSI, NSMP and p53-mutant endometrial cancers. (A) Representative immunohistochemical stainings of CD45RO<sup>+</sup>, CD27<sup>+</sup>, T-Bet<sup>+</sup> and TIA-1<sup>+</sup> cells. (B) Average number of positively stained intratumoral cells for each of the markers in the above panel, counted per core within the tumor center, corrected for the number of cells present. (C) Average number of positively stained cells for each of the markers in the above panel, counted per core within the infiltrative margin, corrected for the number of cells present. The numbers of cases analyzed for each molecular subgroup are listed below the <italic>x</italic>-axis. Boxes represent the interquartile range (IQR), with the upper whisker indicating the 75th percentile and the lower whisker the 25th percentile. The median and mean values are indicated by a horizontal line and cross, respectively. Abbreviations: <italic>POLE, POLE</italic>-mutant; MSI, microsatellite unstable; NSMP, no specific molecular profile; p53, p53-mutant. *<italic>p</italic> < 0.05, **<italic>p</italic> < 0.01, ***<italic>p</italic> < 0.001.</p></caption><graphic specific-use="web-only" content-type="color" xlink:href="koni-06-02-1264565-g002"></graphic></fig></p><p>Concordant with our findings in the tumor center, the infiltrative margin of MSI tumors contained more CD45RO<sup>+</sup> lymphocytes (MSI vs NSMP <italic>p</italic> = 0.002, MSI vs p53 <italic>p</italic> = 0.003) and more TIA-1<sup>+</sup> cytolytic T-lymphocytes (MSI vs NSMP <italic>p</italic> = 0.002, <xref ref-type="fig" rid="f0002">Fig. 2C</xref>). NSMP tumors demonstrated more TIA-1<sup>+</sup> lymphocytes compared with p53-mutant tumors (NSMP vs p53 <italic>p</italic> = 0.023). The numbers of CD27<sup>+</sup> and T-Bet<sup>+</sup> cells did not significantly differ between the four molecular subgroups. Data from the combined analyses supported the increased density of CD45RO<sup>+</sup> and TIA-1<sup>+</sup> cells within <italic>POLE</italic>-mutant/MSI tumors (Fig. S2B).</p></sec><sec id="s0002-0003"><title>Increase in infiltration of PD-1<sup>+</sup> and PD-L1<sup>+</sup> lymphocytes in <italic>POLE</italic>-mutant and MSI tumors</title><p>The increased lymphocytic infiltrate of <italic>POLE</italic>-mutant and MSI tumors, in combination with their expected ultramutated (<italic>POLE</italic>-mutant tumors) or hypermutated (MSI tumors) status, prompted us to investigate the presence of PD-1<sup>+</sup> and PD-L1<sup>+</sup> cells within this cohort (<xref ref-type="fig" rid="f0003">Fig. 3A</xref>).
<fig id="f0003" orientation="portrait" position="float"><label>Figure 3.</label><caption><p>Infiltration of PD-1<sup>+</sup> and PD-L1<sup>+</sup> cells in <italic>POLE</italic>-mutant, MSI, NSMP and p53-mutant endometrial cancers. (A) Representative immunohistochemical stainings of PD-1<sup>+</sup> and PD-L1<sup>+</sup> cells. (B) Average number of PD1<sup>+</sup> cells counted per core within the tumor center, corrected for the number of cells present. (C) Percentage of PD-L1<sup>+</sup> tumor-infiltrating immune cells within the tumor core and infiltrative margin core. (D) Average number of PD1<sup>+</sup> stained cells counted per core within the infiltrative margin. The numbers of cases analyzed for each molecular subgroup are listed below the x-axis. Boxes represent the interquartile range (IQR), with the upper whisker indicating the 75th percentile and the lower whisker the 25th percentile. The median and mean values are indicated by a horizontal line and cross, respectively. Abbreviations: <italic>POLE, POLE</italic>-mutant; MSI, microsatellite unstable; NSMP, no specific molecular profile; p53, p53-mutant. *<italic>p</italic> < 0.05, **<italic>p</italic> < 0.01, ***<italic>p</italic> < 0.001.</p></caption><graphic specific-use="web-only" content-type="color" xlink:href="koni-06-02-1264565-g003"></graphic></fig></p><p>The tumor center of <italic>POLE</italic>-mutant and MSI tumors harbored high numbers of PD-1<sup>+</sup> immune cells (<italic>POLE</italic> vs NSMP <italic>p</italic> < 0.001, <italic>POLE</italic> vs p53 <italic>p</italic> = 0.050, and MSI vs NSMP <italic>p</italic> = 0.003, <xref ref-type="fig" rid="f0003">Fig. 3B</xref>). This was supported by the combined analysis (Fig. S3A). Based on a median of 14.0 PD-1<sup>+</sup> cells/core in all patients, 73% of <italic>POLE</italic>-mutant, 69% of MSI, 31% of NSMP and 48% of p53-mutant tumors were categorized as highly infiltrated with PD-1<sup>+</sup> cells.</p><p><italic>POLE</italic>-mutant and MSI tumors showed markedly increased infiltration of PD-L1<sup>+</sup> immune cells within the tumor center compare with NSMP and p53-mutant tumors (<italic>POLE</italic> vs NSMP <italic>p</italic> < 0.001, <italic>POLE</italic> vs p53 <italic>p</italic> < 0.001, MSI vs NSMP <italic>p</italic> < 0.001, MSI vs p53 <italic>p</italic> = 0.002, <xref ref-type="fig" rid="f0003">Fig. 3C</xref>). The combined analysis showed similar results (Fig. S3B). In total, 100% of <italic>POLE</italic>-mutant, 71% of MSI, 18% of NSMP and 29% of p53-mutant tumors were categorized as PD-L1<sup>+</sup> (based on the immune score). Strikingly, only one tumor sample, a p53-mutant EC, contained PD-L1 expressing tumor cells (noted as a positive tumor score, data not shown).</p><p>Within the infiltrative margin, only the <italic>POLE</italic>-mutant subgroup showed high densities of PD-1<sup>+</sup> immune cells (<italic>POLE</italic> vs NSMP <italic>p</italic> = 0.008, <italic>POLE</italic> vs p53 <italic>p</italic> = 0.007, <xref ref-type="fig" rid="f0003">Fig. 3D</xref>). Combined analysis supported the presence of high numbers of PD-1<sup>+</sup> cells within the <italic>POLE</italic>-mutant/MSI group compare with the NSMP/p53-mutant group (Fig. S3C).</p></sec><sec id="s0002-0004"><title>PD-L1 is preferentially expressed on myeloid cells</title><p>Recently, several studies have shown PD-L1 expression on tumor-associated myeloid cells.<xref rid="cit0001" ref-type="bibr"><sup>1,27-30</sup></xref> Therefore, to determine whether this was also the case for our cohort, we performed two multi-color immunofluorescence stainings on consecutive whole slides of a highly infiltrated <italic>POLE</italic>-mutant tumor sample using the following combinations of monoclonal antibodies: CD68–CD163 – epithelial cell marker cytokeratin, and PD-L1–PD-1, respectively (<xref ref-type="fig" rid="f0004">Fig. 4</xref>). CD68<sup>+</sup> and/or CD163<sup>+</sup> myeloid cells (including macrophages and myeloid dendritic cells) were found in the stromal regions within the center of the tumor, demarcated by the cytokeratin<sup>+</sup> tumor cells (<xref ref-type="fig" rid="f0004">Fig. 4A</xref>). PD-1<sup>+</sup> and PD-L1<sup>+</sup> cells were seen in close proximity, also predominantly located in the intratumoral stromal areas (<xref ref-type="fig" rid="f0004">Fig. 4B</xref>). A co-immunofluorescent staining of PD-1 and CD8 shows frequent co-localization, indicating that PD-1 can be expressed by (cytotoxic) T cells (Fig. S4). PD-L1 expression co-localized with CD68 and CD163, supporting the idea that in our cohort PD-L1 is not mainly expressed by tumor cells but by myeloid cells (<xref ref-type="fig" rid="f0004">Fig. 4C and D</xref>).
<fig id="f0004" orientation="portrait" position="float"><label>Figure 4.</label><caption><p>Immunofluorescent stainings of PD-1, PD-L1 and myeloid markers. Representative image of a <italic>POLE</italic>-mutant endometrial cancer stained with keratin (green)–CD163 (blue)–CD68 (red) in (A), and PD-1 (green)–PD-L1 (blue) in (B). The two triple immunofluorescent stainings from A and B, performed on sequentially cut slides, are layered in (C), with single channel markers for the inset in (D), with keratin (green), PD-L1 (blue), CD68 (red) and CD163 (yellow), demonstrating the co-localization of PD-L1 with myeloid markers.</p></caption><graphic specific-use="web-only" content-type="color" xlink:href="koni-06-02-1264565-g004"></graphic></fig></p></sec><sec id="s0002-0005"><title>TCGA RNA sequencing data demonstrates higher expression of CD8A, CD3E, ITGAE (CD103), MS4A1 (CD20), PTPRC (CD45RO), CD27,TBX21 (T-Bet) and PDCD1 (PD-1) in <italic>POLE</italic>-mutant and MSI tumors</title><p>Next, we compared our data with the expression of above-described immune markers in The Cancer Genome Atlas (TCGA) cancer cohort, which was originally used to devise the molecular classification of EC (<xref ref-type="fig" rid="f0005">Fig. 5</xref>).<xref rid="cit0019" ref-type="bibr"><sup>19</sup></xref> Previously, we have shown higher expression of, among others, CD3E, CD8A, TBX21 (T-Bet) and PDCD1 (PD-1) in <italic>POLE</italic>-mutant compared with MSI and MSS tumors.<xref rid="cit0020" ref-type="bibr"><sup>20</sup></xref> We now extend this analysis to specifically compare the four proposed prognostic subgroups.<xref rid="cit0019" ref-type="bibr"><sup>19</sup></xref> Of the 244 informative samples, the TCGA cohort included 18 <italic>POLE</italic>-mutant, 69 MSI, 96 NSMP and 62 <italic>TP53</italic>-mutant. Analysis of the RNA sequencing data of this cohort demonstrated higher expression of CD8A, CD3E, ITGAE (CD103), MS4A1 (CD20), PTPRC (CD45RO), CD27,TBX21 (T-Bet) and PDCD1 (PD-1) in <italic>POLE</italic>-mutant and MSI tumors compare with NSMP and <italic>TP53</italic>-mutant. TIA-1 expression did not differ between the four molecular subgroups. <italic>POLE</italic>-mutant ECs showed a trend toward increased expression of CD274 (PD-L1) (<italic>p</italic> = 0.057).
<fig id="f0005" orientation="portrait" position="float"><label>Figure 5.</label><caption><p>Expression of immune markers in according to tumor molecular subtype in TCGA series. RSEM normalized RNAseq data were log2 transformed and analyzed according to tumor molecular subtype. Boxes represent the interquartile range (IQR), with the upper whisker indicating the 75th percentile and the lower whisker the 25th percentile. The median and mean values are indicated by a horizontal line and cross, respectively. Abbreviations: <italic>POLE, POLE</italic>-mutant; MSI, microsatellite unstable; NSMP, no specific molecular profile; p53, p53-mutant. *<italic>p</italic> < 0.05, **<italic>p</italic> < 0.01, ***<italic>p</italic> < 0.001.</p></caption><graphic specific-use="web-only" content-type="color" xlink:href="koni-06-02-1264565-g005"></graphic></fig></p></sec><sec id="s0002-0006"><title>Patients with <italic>POLE</italic>-mutated and MSI tumors have higher numbers of predicted neoantigens, regardless of their immune infiltration status</title><p>The presence of a subset of <italic>POLE</italic>-mutant and MSI tumors with a relatively low immune infiltration and NSMP and <italic>TP53</italic>-mutant tumors with a relatively high immune infiltration led us to evaluate the relationship between immune infiltrate and numbers of predicted neoantigens within the TCGA cohort (<xref ref-type="fig" rid="f0006">Fig. 6</xref>). First of all, we demonstrated the presence of higher numbers of expected neoantigens in <italic>POLE</italic>-mutant and MSI tumors compared with NSMP and <italic>TP53</italic>-mutant tumors (<xref ref-type="fig" rid="f0006">Fig. 6A</xref>). The molecular subgroups were dichotomized according to CD8A expression from RNAseq data, with high infiltration defined as expression above the median of the respective molecular subgroup. Subsequently, we quantified predicted neoantigens for high and low infiltrated tumors within the molecular subgroups (<xref ref-type="fig" rid="f0006">Fig. 6B</xref>). No differences were found in the numbers of predicted neoantigens between samples with high or low CD8A expression within the molecular subgroups.
<fig id="f0006" orientation="portrait" position="float"><label>Figure 6.</label><caption><p>Predicted number of HLA-A2-binding neoantigens across the four molecular subgroups in The Cancer Genome Atlas endometrial cancer cohort. (A) Comparison between the number of predicted HLA-A2 binding neoantigens in <italic>POLE</italic>-mutant, MSI, NSMP and <italic>TP53</italic>-mutant subgroups based on RNAseq. (B) Comparison between patients with high and low infiltration (based on CD8A expression from RNAseq, relative to median within the group) of lymphocytes within <italic>POLE</italic>-mutant, MSI, NSMP and <italic>TP53</italic>-mutant subgroups. The numbers of cases analyzed for each molecular subgroup are listed below the x-axis. Boxes represent the interquartile range (IQR), with upper whisker indicating the 75th percentile and the lower whisker the 25th percentile. The median and mean values are indicated by a horizontal line and cross, respectively. Abbreviations: <italic>POLE, POLE</italic>-mutant; MSI, microsatellite unstable; NSMP, no specific molecular profile; p53, p53-mutant. *<italic>p</italic> < 0.05, **<italic>p</italic> < 0.01, ***<italic>p</italic> < 0.001.</p></caption><graphic specific-use="web-only" content-type="color" xlink:href="koni-06-02-1264565-g006"></graphic></fig></p></sec></sec><sec sec-type="discussion" id="s0003"><title>Discussion</title><p>In this study we demonstrate the presence of high numbers of tumor-infiltrating T cells in <italic>POLE</italic>-mutant and MSI tumors, both predicted to be neoantigen-rich, from a clinically relevant cohort of high-risk EC patients. Moreover, these two molecular subtypes harbor high densities of PD-1- and PD-L1-expressing immune cells, rendering them attractive candidates for immune checkpoint inhibition strategies.</p><p>The presence of a prominent immune infiltrate in <italic>POLE</italic>-mutant and MSI high-risk EC is in concordance with our previous findings in a pre-selected cohort including 47 <italic>POLE</italic>-mutant, 49 microsatellite unstable and 54 microsatellite stable tumors, in which we demonstrated that <italic>POLE</italic>-mutant tumors, and to a lesser extent MSI tumors, are characterized by a robust intratumoral T-cell response.<xref rid="cit0020" ref-type="bibr"><sup>20</sup></xref> These initial findings have recently been extended to other unselected EC cohorts, in which high densities of peritumoral and tumor-infiltrating T-lymphocytes have been described in <italic>POLE</italic>-mutant tumors.<xref rid="cit0021" ref-type="bibr"><sup>21,22,31</sup></xref> High expression of PD-1 and PD-L1 on intraepithelial immune cells in <italic>POLE</italic>-mutant and MSI ECs has previously been suggested by Howitt et al, albeit in a cohort which included only three <italic>POLE</italic>-mutant cases.<xref rid="cit0021" ref-type="bibr"><sup>21</sup></xref> An interesting difference between the data presented by Howitt et al. and the present study is the expression of PD-L1 on tumor cells. Howitt et al. describe that 20% of ECs (<italic>POLE</italic>-mutant, MSI and MSS) show PD-L1<sup>+</sup> tumor cells, whereas within our high-risk cohort only 1 out of 116 tumors showed any expression of PD-L1 on the tumor cells (using the same PD-L1 antibody). Our use of tissue microarrays may have led to an underestimation of PD-L1 expressing tumor cells, as PD-L1 expression is known to be heterogeneously distributed.<xref rid="cit0032" ref-type="bibr"><sup>32</sup></xref> Moreover, consecutive full slides of one <italic>POLE</italic>-mutant case were stained using multi-color immunofluorescence: PD-L1 expression was predominantly found in the intratumoral stromal regions in close proximity with PD-1<sup>+</sup> cells. Furthermore, PD-L1 expression co-localized with CD68 and CD163, suggesting that in this case PD-L1 is primarily expressed by myeloid cells rather than tumor cells. PD-L1<sup>+</sup> immune cells have previously been described by (among others) Heeren et al. and Herbst et al.; the latter also showed that PD-L1 positivity on immune cells, but not on tumor cells, was associated with response to immune checkpoint inhibition.<xref rid="cit0001" ref-type="bibr"><sup>1,28</sup></xref></p><p>Comparisons of outcomes from our immunohistochemical analyses in the TransPORTEC high-risk cohort and analyses of the RNA sequencing data from The Cancer Genome Atlas (TCGA) showed similar results for five out of ten markers, namely CD3, CD8<sup>+</sup>, CD103, CD45RO and PD1. The immunohistochemical analyses of the TransPORTEC cohort did not reveal significant differences in numbers of CD20<sup>+</sup> and CD27<sup>+</sup> cells between the four molecular subgroups, while analysis of the TCGA cohort demonstrated increased expression of CD20<sup>+</sup> and CD27<sup>+</sup> cells within the <italic>POLE</italic>-mutant and MSI subgroups. This inconsistency may be attributed to the use of a TMA for immunohistochemical analyses of CD20<sup>+</sup> and CD27<sup>+</sup> cells. These immune cells frequently reside in tertiary lymphoid structures in the myometrium, which are frequently seen in <italic>POLE</italic>-mutant tumors.<xref rid="cit0020" ref-type="bibr"><sup>20,33-35</sup></xref> The areas containing these structures may not have been present in the TMA. Second, outcomes regarding TIA-1, T-Bet and PD-L1 positivity were discordant. These differences may be due to the known discrepancy between mRNA and protein expression.<xref rid="cit0036" ref-type="bibr"><sup>36</sup></xref> Another possible explanation for these discrepancies may be the relatively high proportion of clear cell EC (15.5%) within the TransPORTEC high-risk cohort, while only endometrioid, serous and mixed histologies were included in the TCGA study.</p><p>The presence of high numbers of CD8<sup>+</sup> and PD-1<sup>+</sup> cells in <italic>POLE</italic>-mutant and MSI tumors may suggest the presence of high numbers of tumor-specific T cells targeting neoantigens within these subgroups of patients. Similarly, our analysis of the TCGA EC cohort demonstrates that <italic>POLE</italic>-mutant and MSI tumors are characterized by a significantly higher number of mutations predicted to result in major histocompatibility complex-binding neoantigens, and a correspondingly higher number of tumor-infiltrating CD8<sup>+</sup> T cells, as assessed by CD8A mRNA levels. This link between neoantigen accumulation and infiltration by immune cells is supported by a recent genomic characterization of colorectal cancers, in which an association between high neoantigen load, overall lymphocytic infiltration, tumor-infiltrating lymphocytes and survival was demonstrated.<xref rid="cit0010" ref-type="bibr"><sup>10</sup></xref></p><p>Surprisingly, the number of predicted immunogenic mutations did not directly reflect the levels of CD8A mRNA expression within each molecular subgroup (<xref ref-type="fig" rid="f0006">Fig. 6</xref>). Similarly, in our immunohistochemical analysis, we found MSI tumors, expected to be neoantigen-rich, with almost no signs of CD8<sup>+</sup> T-cell infiltration, and p53-mutant tumors, expected to have low numbers of neoantigens, with an enhanced intratumoral immune response. One explanation for this apparent discrepancy between immune infiltration and the number of predicted neoantigens could be that the nature (i.e., clonal vs subclonal) of the neoepitopes, instead of the crude number of predicted neoantigens, determine the degree of immune response.<xref rid="cit0013" ref-type="bibr"><sup>13</sup></xref> Another explanation may be that within our analyses only predicted binding to HLA-A*02:01 was taken into account rather than to individual HLA alleles. Furthermore, immune responses may be impeded by impairment of major histocompatibility complex (MHC) class I expression due to mutations in HLA, β-2 microglobulin and JAK-1 in highly mutated ECs.<xref rid="cit0020" ref-type="bibr"><sup>20,37</sup></xref> Therefore, a logical next step in understanding the interaction between neoepitopes and immune response within the four molecular subgroups would be the direct identification and characterization of tumor-specific T cells targeting these neoantigens, as has recently been performed by Gros et al. in melanoma.<xref rid="cit0024" ref-type="bibr"><sup>24</sup></xref></p><p>With regard to the p53-mutant tumors with an enhanced antitumor immune response despite low expected neoantigen load, we hypothesize that this response may be aimed at self-antigens or cancer/testis antigens instead of neoepitopes. Taking into account their unfavorable survival outcomes, further investigation of the highly infiltrated p53-mutant subset will be of great interest as this may provide new insight in the selection of candidates for immune checkpoint therapies.</p><p>The data on mutational load, neoantigens and immune infiltration reported by us and others suggest that checkpoint inhibition may be a strategy of particular interest for treating advanced stage patients with <italic>POLE</italic>-mutant and MSI tumors. Recent case reports provide proof of principle by demonstrating the efficacy of anti-PD-1 inhibitors in a limited number of advanced stage <italic>POLE</italic>-mutant or mismatch repair deficient cancers.<xref rid="cit0007" ref-type="bibr"><sup>7,25,26</sup></xref> Moreover, a Phase II trial evaluating immune related objective responses to Pembrolizumab in patients with or without mismatch repair (MMR) deficiency, demonstrated objective responses in 40% of patients with MMR deficient colorectal cancer and 71% of patients with MMR deficient non-colorectal cancers (including two ECs). Contrastingly, no objective responses were observed in the MMR proficient colorectal cancers. Moreover, data from this study adds to the growing body of evidence suggesting that high numbers of somatic mutations (in this case due to MMR deficiency) and high numbers of predicted neoantigens play an important role in the sensitivity to checkpoint inhibition.<xref rid="cit0011" ref-type="bibr"><sup>11-13,15</sup></xref> Furthermore, an in-depth analysis of patients treated with anti-PD-1 therapy prioritized PD-L1 expression as being the most closely associated with objective tumor regression.<xref rid="cit0038" ref-type="bibr"><sup>38</sup></xref> Further analyses of non-responders may uncover other mutations affecting epitope presentation, T-cell infiltration and response to checkpoint inhibition.</p><p>From a clinical point of view, as checkpoint inhibitors are associated with significant costs and potential toxicities, it is essential to select individual patients that will benefit from these therapies. Patients with low/intermediate-risk disease carrying <italic>POLE</italic> mutations have an excellent prognosis under standard treatment, and therefore checkpoint inhibition is unlikely to be appropriate for this group.<xref rid="cit0019" ref-type="bibr"><sup>19,39-41</sup></xref> However, (although infrequently occurring) <italic>POLE</italic>-mutant and MSI patients with recurring or metastatic disease are possible candidates.<xref rid="cit0007" ref-type="bibr"><sup>7,25,26</sup></xref> Clinical trials, in which high-risk EC patients are grouped according to molecular subtype, will be required to determine clinical benefit of immunotherapy.</p><p>Importantly, the data thus far regarding <italic>POLE</italic>-mutant EC may be applicable to other tumor types harboring <italic>POLE</italic> mutations. While <italic>POLE</italic> mutations are found in 7–12% of EC, they are also found in other malignancies including colorectal cancers, cancers of the brain, breast, pancreas and stomach, albeit at lower frequencies.<xref rid="cit0019" ref-type="bibr"><sup>19,39,42-48</sup></xref> Although a prognostic advantage of this mutation has now been established in glioblastoma and stage II/III colorectal cancer, patients with recurrent or metastatic hypermutated disease may also benefit from immunotherapeutic strategies such as checkpoint inhibitors as proposed for EC.<xref rid="cit0007" ref-type="bibr"><sup>7,47,49</sup></xref> Basket trials stratifying patients according to tumor molecular alterations such as <italic>POLE</italic> mutations should be initiated to investigate whether these patients may also benefit from checkpoint inhibition.</p><p>In summary, taking into account the strong immune infiltration, high numbers of PD-1<sup>+</sup> and PD-L1<sup>+</sup> lymphocytes, large numbers of somatic mutations and neoantigens, and the recently demonstrated clinical efficacy in these cohorts of patients, <italic>POLE</italic>-mutant and MSI tumors are expected to benefit from checkpoint inhibition.<xref rid="cit0021" ref-type="bibr"><sup>21,25,50</sup></xref></p></sec><sec sec-type="methods" id="s0004"><title>Methods</title><sec id="s0004-0001"><title>Selection of patients and tissues</title><p>A previously described cohort of 116 high-risk EC patients was used in this study (<xref ref-type="table" rid="t0001">Table 1</xref>).<xref rid="cit0042" ref-type="bibr"><sup>42</sup></xref> In brief, tumor tissues from high-risk EC patients were selected from partner institutions of the TransPORTEC consortium using inclusion criteria of the PORTEC-3 study. Patients included in the PORTEC-3 had EC with one of the following FIGO 2009 stages and grade: 1A grade 3 with myometrial and lymphovascular space invasion; IB grade 3; II, IIIA or IIIC; IIIB if only parametrial invasion; stage IA (with invasion), 1B, II or III with serous or clear cell histology.<xref rid="cit0051" ref-type="bibr"><sup>51</sup></xref><table-wrap id="t0001" orientation="portrait" position="float"><label>Table 1.</label><caption><p>Clinicopathological characteristics of the high-risk endometrial cancer patient cohort.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment><table frame="hsides" rules="groups"><colgroup><col width="20pt" align="left"></col><col width="20pt" align="left"></col><col width="20pt" align="left"></col><col width="20pt" align="left"></col><col width="20pt" align="left"></col><col width="20pt" align="left"></col><col width="20pt" align="left"></col><col width="20pt" align="left"></col><col width="20pt" align="left"></col><col width="20pt" align="left"></col><col width="20pt" align="left"></col><col width="20pt" align="left"></col></colgroup><thead><tr><th rowspan="2" align="left"> </th><th colspan="2" align="center">All patients</th><th colspan="2" align="center"><italic>POLE</italic>-mutant</th><th colspan="2" align="center">MSI</th><th colspan="2" align="center">NSMP</th><th colspan="2" align="center">p53-mutant</th><th rowspan="2" align="left"> </th></tr><tr><th colspan="2" align="center"><italic>N</italic> = 116<hr></hr></th><th colspan="2" align="center"><italic>N</italic> = 15<hr></hr></th><th colspan="2" align="center"><italic>N</italic> = 19<hr></hr></th><th colspan="2" align="center"><italic>N</italic> = 42<hr></hr></th><th colspan="2" align="center"><italic>N</italic> = 40<hr></hr></th></tr><tr><th align="left"> </th><th align="center"><italic>N</italic></th><th align="center">%</th><th align="center"><italic>N</italic></th><th align="center">%</th><th align="center"><italic>N</italic></th><th align="center">%</th><th align="center"><italic>N</italic></th><th align="center">%</th><th align="center"><italic>N</italic></th><th align="center">%</th><th align="left"><italic>p</italic>-value</th></tr></thead><tbody><tr><td colspan="12" align="left">Age at diagnosis (years)</td></tr><tr><td align="left">Mean (range)</td><td colspan="2" align="center">66 (21–85)</td><td colspan="2" align="center">61 (49–80)</td><td colspan="2" align="center">65 (49–82)</td><td colspan="2" align="center">64 (21–84)</td><td colspan="2" align="center">71 (45–85)</td><td align="left">0.004</td></tr><tr><td colspan="12" align="left">Stage</td></tr><tr><td align="left">I</td><td align="char" char=".">42</td><td align="char" char=".">36.2</td><td align="char" char=".">8</td><td align="char" char=".">53.3</td><td align="char" char=".">5</td><td align="char" char=".">26.3</td><td align="char" char=".">16</td><td align="char" char=".">38.1</td><td align="char" char=".">13</td><td align="char" char=".">32.5</td><td align="left">0.246</td></tr><tr><td align="left">II</td><td align="char" char=".">21</td><td align="char" char=".">18.1</td><td align="char" char=".">3</td><td align="char" char=".">20.0</td><td align="char" char=".">2</td><td align="char" char=".">10.5</td><td align="char" char=".">12</td><td align="char" char=".">28.6</td><td align="char" char=".">4</td><td align="char" char=".">10.0</td><td align="left"> </td></tr><tr><td align="left">III</td><td align="char" char=".">41</td><td align="char" char=".">35.3</td><td align="char" char=".">3</td><td align="char" char=".">20.0</td><td align="char" char=".">10</td><td align="char" char=".">52.6</td><td align="char" char=".">11</td><td align="char" char=".">26.2</td><td align="char" char=".">17</td><td align="char" char=".">42.5</td><td align="left"> </td></tr><tr><td align="left">IV</td><td align="char" char=".">11</td><td align="char" char=".">9.5</td><td align="char" char=".">1</td><td align="char" char=".">6.7</td><td align="char" char=".">2</td><td align="char" char=".">10.5</td><td align="char" char=".">3</td><td align="char" char=".">7.1</td><td align="char" char=".">5</td><td align="char" char=".">12.5</td><td align="left"> </td></tr><tr><td align="left">Unknown</td><td align="char" char=".">1</td><td align="char" char=".">0.9</td><td align="char" char=".">0</td><td align="char" char=".">0.0</td><td align="char" char=".">0</td><td align="char" char=".">0.0</td><td align="char" char=".">0</td><td align="char" char=".">0.0</td><td align="char" char=".">1</td><td align="char" char=".">2.5</td><td align="left"> </td></tr><tr><td colspan="12" align="left">Tumor type</td></tr><tr><td align="left">Endometrioid</td><td align="char" char=".">86</td><td align="char" char=".">74.1</td><td align="char" char=".">14</td><td align="char" char=".">93.3</td><td align="char" char=".">17</td><td align="char" char=".">89.5</td><td align="char" char=".">35</td><td align="char" char=".">83.3</td><td align="char" char=".">20</td><td align="char" char=".">50.0</td><td align="left"><0.001</td></tr><tr><td align="left">Serous</td><td align="char" char=".">12</td><td align="char" char=".">10.3</td><td align="char" char=".">0</td><td align="char" char=".">0.0</td><td align="char" char=".">0</td><td align="char" char=".">0.0</td><td align="char" char=".">0</td><td align="char" char=".">0.0</td><td align="char" char=".">12</td><td align="char" char=".">30.0</td><td align="left"> </td></tr><tr><td align="left">Clearcell</td><td align="char" char=".">18</td><td align="char" char=".">15.5</td><td align="char" char=".">1</td><td align="char" char=".">6.7</td><td align="char" char=".">2</td><td align="char" char=".">10.5</td><td align="char" char=".">7</td><td align="char" char=".">16.7</td><td align="char" char=".">8</td><td align="char" char=".">20.0</td><td align="left"> </td></tr><tr><td colspan="12" align="left">Grade</td></tr><tr><td align="left">1</td><td align="char" char=".">13</td><td align="char" char=".">11.2</td><td align="char" char=".">0</td><td align="char" char=".">0.0</td><td align="char" char=".">2</td><td align="char" char=".">10.5</td><td align="char" char=".">8</td><td align="char" char=".">19.0</td><td align="char" char=".">3</td><td align="char" char=".">7.5</td><td align="left">0.036</td></tr><tr><td align="left">2</td><td align="char" char=".">5</td><td align="char" char=".">4.3</td><td align="char" char=".">1</td><td align="char" char=".">6.7</td><td align="char" char=".">3</td><td align="char" char=".">15.8</td><td align="char" char=".">1</td><td align="char" char=".">2.4</td><td align="char" char=".">0</td><td align="char" char=".">0.0</td><td align="left"> </td></tr><tr><td align="left">3</td><td align="char" char=".">98</td><td align="char" char=".">84.5</td><td align="char" char=".">14</td><td align="char" char=".">93.3</td><td align="char" char=".">14</td><td align="char" char=".">73.7</td><td align="char" char=".">33</td><td align="char" char=".">78.6</td><td align="char" char=".">37</td><td align="char" char=".">92.5</td><td align="left"> </td></tr><tr><td colspan="12" align="left">Lymphovascular space invasion</td></tr><tr><td align="left">Yes</td><td align="char" char=".">55</td><td align="char" char=".">47.4</td><td align="char" char=".">6</td><td align="char" char=".">40</td><td align="char" char=".">15</td><td align="char" char=".">78.9</td><td align="char" char=".">18</td><td align="char" char=".">42.9</td><td align="char" char=".">16</td><td align="char" char=".">40</td><td align="left">0.103</td></tr><tr><td align="left">No</td><td align="char" char=".">40</td><td align="char" char=".">34.5</td><td align="char" char=".">9</td><td align="char" char=".">60.0</td><td align="char" char=".">2</td><td align="char" char=".">10.5</td><td align="char" char=".">18</td><td align="char" char=".">42.9</td><td align="char" char=".">11</td><td align="char" char=".">27.5</td><td align="left"> </td></tr><tr><td align="left">Unknown</td><td align="char" char=".">21</td><td align="char" char=".">18.1</td><td align="char" char=".">0</td><td align="char" char=".">0.0</td><td align="char" char=".">2</td><td align="char" char=".">10.5</td><td align="char" char=".">6</td><td align="char" char=".">14.3</td><td align="char" char=".">13</td><td align="char" char=".">32.5</td><td align="left"> </td></tr><tr><td colspan="12" align="left">Depth of myometrial invasion</td></tr><tr><td align="left"><50%</td><td align="char" char=".">23</td><td align="char" char=".">19.8</td><td align="char" char=".">4</td><td align="char" char=".">26.7</td><td align="char" char=".">2</td><td align="char" char=".">10.5</td><td align="char" char=".">6</td><td align="char" char=".">14.3</td><td align="char" char=".">11</td><td align="char" char=".">27.5</td><td align="left">0.261</td></tr><tr><td align="left">>50%</td><td align="char" char=".">87</td><td align="char" char=".">75.0</td><td align="char" char=".">11</td><td align="char" char=".">73.3</td><td align="char" char=".">17</td><td align="char" char=".">89.5</td><td align="char" char=".">33</td><td align="char" char=".">78.6</td><td align="char" char=".">26</td><td align="char" char=".">65.0</td><td align="left"> </td></tr><tr><td align="left">Unknown</td><td align="char" char=".">6</td><td align="char" char=".">5.2</td><td align="char" char=".">0</td><td align="char" char=".">0.0</td><td align="char" char=".">0</td><td align="char" char=".">0.0</td><td align="char" char=".">3</td><td align="char" char=".">7.1</td><td align="char" char=".">3</td><td align="char" char=".">7.5</td><td align="left"> </td></tr><tr><td colspan="12" align="left">Adjuvant therapy</td></tr><tr><td align="left">Yes</td><td align="char" char=".">82</td><td align="char" char=".">70.7</td><td align="char" char=".">14</td><td align="char" char=".">93.3</td><td align="char" char=".">15</td><td align="char" char=".">78.9</td><td align="char" char=".">33</td><td align="char" char=".">78.6</td><td align="char" char=".">20</td><td align="char" char=".">50.0</td><td align="left">0.134</td></tr><tr><td align="left">No</td><td align="char" char=".">10</td><td align="char" char=".">8.6</td><td align="char" char=".">1</td><td align="char" char=".">6.7</td><td align="char" char=".">1</td><td align="char" char=".">5.3</td><td align="char" char=".">2</td><td align="char" char=".">4.8</td><td align="char" char=".">6</td><td align="char" char=".">15.0</td><td align="left"> </td></tr><tr><td align="left">Unknown</td><td align="char" char=".">24</td><td align="char" char=".">20.7</td><td align="char" char=".">0</td><td align="char" char=".">0.0</td><td align="char" char=".">3</td><td align="char" char=".">15.8</td><td align="char" char=".">7</td><td align="char" char=".">16.7</td><td align="char" char=".">14</td><td align="char" char=".">35.0</td><td align="left"> </td></tr></tbody></table><table-wrap-foot><fn><p>Characteristics are shown for the whole group, as well as for each of the molecular subgroups analyzed. Abbreviations: MSI, microsatellite unstable; NSMP, no specific molecular profile.</p></fn></table-wrap-foot></table-wrap></p></sec><sec id="s0004-0002"><title>Construction of tissue microarray</title><p>Morphologically representative paraffin-embedded tissue blocks containing at least 70% tumor cells were selected by two experienced gyneco-pathologists (VS and TB). The selected tumor blocks were used to construct (and validate) a Tissue Microarray (TMA) as previously described.<xref rid="cit0042" ref-type="bibr"><sup>42</sup></xref> One millimeter-sized tumor (center of the tumor) and tumor/stroma (invasive margin) cores of each tumor block were randomly distributed on the TMA in triplicate.</p></sec><sec id="s0004-0003"><title>Assessment of <italic>POLE</italic>, MSI, p53 and NSMP status</title><p>Classification of patients into the four molecular subgroups was performed as previously described.<xref rid="cit0042" ref-type="bibr"><sup>42</sup></xref> In brief, tumor DNA isolation was performed fully automated using the Tissue Preparation System (Siemens Healthcare Diagnostics).<xref rid="cit0052" ref-type="bibr"><sup>52</sup></xref> Bi-directional Sanger sequencing was used to screen exons 9, 13 and 14 of the <italic>POLE</italic> exonuclease domain for somatic mutations. Microsatellite instability and p53 mutational status were determined as previously described.<xref rid="cit0042" ref-type="bibr"><sup>42,53</sup></xref></p></sec><sec id="s0004-0004"><title>Immunohistochemistry</title><p>TMA sections were deparaffinized and rehydrated. Antigen retrieval was performed using 0.01M citrate buffer pH 6.0, and endogenous peroxidase activity was blocked. Slides were incubated overnight at room temperature (CD3, TIA-1, T-Bet and PD-1), for 1 h at room temperature (CD8<sup>+</sup>, CD20) or overnight at 4 °C (CD103) with primary antibodies against CD3 (1:100, clone PS-1, Diagnostic BioSystems), CD8<sup>+</sup> (1:50, clone C8/144B, DAKO), CD20 (1:200, clone L26, DAKO), CD103 (1:200, Integrin αEβ7, Abcam), TIA-1 (1:200, clone 2G9A10F5, Beckman Coulter), T-bet (1:400 in 10% normal goat serum, sc-21003, Santa Cruz Biotechnology), PD-1 (1:200, AF1086, R&D), and PD-L1 (1 µg/mL, clone E1L3N, Cell Signaling Technology). Slides were incubated with BrightVision Poly-HRP (poly-HRP-GAM/R/R, DPV0110HRP, Immunologic; CD3, TIA-1, T-bet), a goat HRP-polymer kit (GHP516H, Biocare Medical; PD-1), anti-mouse secondary antibody (K4007, DAKO, CD8<sup>+</sup>, CD20) or anti-rabbit secondary antibody (K4011, DAKO, CD103) for 30 min. For CD103, a slightly different method using avidin/biotin blocking was used as described previously.<xref rid="cit0054" ref-type="bibr"><sup>54</sup></xref> PD-L1 staining was performed using the Ventrana Discovery Ultra Platform for automatic staining, detection was performed using the Discovery Amp-HQ kit (tyramide-based amplification). Antibody binding was visualized with 3,3′-diamino-benzidine-tetrahydrochloride (DAB) and haematoxylin counterstaining. Slides were dehydrated and mounted before digitalization (Ultra Fast Scanner 1.6 RA. Philips or ScanScope, Aperio technologies) and analysis.</p></sec><sec id="s0004-0005"><title>Quantification of IHC</title><p>Total numbers of CD3<sup>+</sup>, CD8<sup>+</sup>, CD103<sup>+</sup>, CD27<sup>+</sup>, TIA-1<sup>+</sup>, T-Bet<sup>+</sup>, CD20<sup>+</sup>, CD45RO<sup>+</sup> and PD-1<sup>+</sup> cell numbers were quantified per core. The percentage of tumor and stroma surface area within each core were estimated, and used to extrapolate cell counts to 100% surface area. Cores taken from the tumor center were included in the analysis if at least two out of the three cores contained >20% tumor. Cores from the infiltrative margin were included in the analysis if at least two out of the three cores contained >20% stroma and if there was tumor tissue present. Average cell counts per 100% surface area were recorded for the tumor center and infiltrative margin. Slides were counted manually by two individuals (FE and IG) that were blinded for other clinicopathological data. Inter-observer variation was evaluated by Spearman rank correlation (median <italic>R</italic><sup>2</sup> 0.935, range 0.682–0.988).</p><p>Quantification of PD-L1 was evaluated on tumor-infiltrating immune cells and tumor cells as previously described.<xref rid="cit0001" ref-type="bibr"><sup>1</sup></xref> In brief, the proportion of PD-L1 expressing tumor cells (tumor score) was noted as a percentage of the total number of tumor cells within that core. Due to very low expression of PD-L1 it was decided to consider any expression of PD-L1 on tumor cells as positive. Furthermore, the percentage of tumor-infiltrating immune cells (immune score) with moderate to strong PD-L1 expression was registered. Immune cells were defined positive when cells displayed clearly visible cytoplasmic and/or membranous staining. Patients were included in the analysis if at least two out of three cores were evaluated; the final score was based on the core with the highest PD-L1 expression. For the analyses of the immune score, PD-L1 positivity was defined as >1% (based on the median score in the cohort).</p></sec><sec id="s0004-0006"><title>Immunofluorescence</title><p>Three combinations of multi-color immunofluorescent stainings were performed as described previously.<xref rid="cit0055" ref-type="bibr"><sup>55</sup></xref> The first combination consisted of anti-CD163 (polyclonal rabbit, ab87099, Abcam), anti-CD68 (monoclonal mouse IgG2a, clone 514H12, ABDserotec) and anti-keratin (monoclonal mouse IgG1, clone AE1/AE3, MAB3412, Millipore). The second combination consisted of anti-PD-L1 (polyclonal rabbit, clone SP142, Roche) and anti-PD1 (monoclonal mouse IgG1, clone NAT105, Abcam), and the third consisted of anti-CD8<sup>+</sup> (mouse monoclonal IgG2b, clone 4B11, Novo Castra) and anti-PD-1 (polyclonal goat, R&D Systems).</p><p>In short, after slides were deparaffinized and rehydrated, antigen retrieval was achieved by microwave oven treatment in a Tris–EDTA buffer at pH 9.0. Slides were incubated with the listed primary antibodies overnight. The following secondary Alexa Fluor labeled antibodies were used for the CD163–CD68–keratin and PD-L1–PD-1 combinations: 647 goat anti-rabbit, 546 goat anti-mouse IgG2a, and 488 goat anti-mouse IgG1 (all from Invitrogen, Life Technologies, Carlsbad, USA). Donkey anti-goat 488 and donkey anti-mouse IgG 647 were used for PD-1/CD8<sup>+</sup> detection. The slides were counterstained with DAPI and coverslipped. Immunofluorescent images were acquired with an LSM700 confocal laser scanning microscope equipped with an LCI Plan-Neofluar 25×/0.8 Imm Korr DIC M27 objective (Zeiss, Göttingen, Germany). Double or triple positivity of cells in the center of the tumor as well as at the invasive margin was determined using LSM Image Browser (version 4.2.0.121, Zeiss). Images from the two triple immunofluorescent stainings were merged using Adobe Photoshop CS6.</p></sec><sec id="s0004-0007"><title>TCGA RNA sequencing</title><p>TCGA RNAseq analysis was performed as previously reported.<xref rid="cit0019" ref-type="bibr"><sup>19,20</sup></xref> Data were downloaded from FireBrowse on November 11, 2014 (<ext-link ext-link-type="uri" xlink:href="http://firebrowse.org/?cohort=UCECanddownload_dialog=true">http://firebrowse.org/?cohort=UCECanddownload_dialog=true</ext-link>). In total, 245 samples with RSEM normalized data were available for analysis.</p></sec><sec id="s0004-0008"><title>Prediction of antigenic neoepitopes</title><p>Prediction of antigenic neoepitopes was performed as previously reported.<xref rid="cit0020" ref-type="bibr"><sup>20</sup></xref> In brief, an algorithm was developed to estimate the immunogenicity of individual tumors in which the following considerations were taken into account: (i) to generate a functional neoepitope a missense mutation must be expressed; (ii) most functional neoepitopes are predicted to bind MHC class I molecules (IC50 < 500 nM) by NetMHCPan.<xref rid="cit0008" ref-type="bibr"><sup>8,56,57</sup></xref>; (iii) the likelihood that a neoepitope is antigenic is reduced if the corresponding wild-type peptide also binds the MHC with similar affinity as T cells to the epitope may be centrally deleted or tolerized.<xref rid="cit0058" ref-type="bibr"><sup>58</sup></xref> Our strategy was similar to that reported by others.<xref rid="cit0008" ref-type="bibr"><sup>8,13,57,59</sup></xref> For each tumor all possible 9mers for every missense mutation in expressed genes (defined as non-zero reads from RNAseq) and the binding affinity of the mutant and corresponding wild-type peptide for HLA-A*02:01 were calculated using NetMHCPan 2.8.<xref rid="cit0056" ref-type="bibr"><sup>56</sup></xref> If several peptides had an IC50 <500 nM, the strongest binder was used for analysis. We defined antigenic mutations as neoepitopes predicted to bind MHC molecules (IC50 < 500 nM) for which the corresponding wild-type peptide was not predicted to bind MHC (IC50 > 500 nM).</p></sec><sec id="s0004-0009"><title>Statistical methods</title><p>Comparison between clinicopathological characteristics of the four molecular subgroups was made using Kruskal–Wallis followed by Mann–Whitney <italic>U</italic> (for age) and χ<sup>2</sup> tests (for all other variables). Correlations between immunohistochemical stainings and the four molecular subgroups were evaluated using Kruskal–Wallis followed by Mann–Whitney <italic>U</italic> tests. The same method was used to evaluate correlations between RNA expression from the TCGA cohort of immune-related genes and the four molecular subgroups. Additionally, analyses were performed combining <italic>POLE</italic>-mutant and MSI samples vs NSMP and p53-mutant samples. All tests were performed two-sided. Significance was defined as a <italic>p</italic>-value of < 0.05. Statistical analyses were performed using IBM SPSS version 22 (SPSS, Inc., Chicago, USA) and GraphPad Prism (GraphPad Software, Inc., CA, USA).</p></sec></sec><sec sec-type="supplementary-material"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="SM5200"><caption><title>KONI_A_1264565_supplementary_data.zip</title></caption><media xlink:href="koni-06-02-1264565-s001.zip" mimetype="application" mime-subtype="zip" orientation="portrait" id="d37e306" position="anchor"></media></supplementary-material></sec></body><back><sec><title>Disclosure of potential conflicts of interest</title><p>No potential conflicts of interest were disclosed.</p></sec><sec><title>Acknowledgments</title><p>The authors would like to thank the members of the PORTEC study group, the patients involved in the PORTEC studies, Mark Glaire for his assistance with quantification of the immunohistochemical stainings, and Annechien Plat and Enno Dreef for their technical assistance.</p></sec><sec><title>Funding</title><p>This work was supported by Dutch Cancer Society/Alpe d'Huzes grant UMCG 2014-6719 to MB; a Dutch Cancer Society Grant (UL2012-5719) to ICG, CLC, TB; and a Jan Kornelis de Cock Stichting grant to FAE. DNC is supported by a Clinician Scientist Award from the Academy of Medical Sciences / Health Foundation, and has received funding from the Oxford Cancer Centre, University of Oxford.</p></sec><ref-list><title>References</title><ref id="cit0001"><label>1.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Herbst</surname><given-names>RS</given-names></name>, <name name-style="western"><surname>Soria</surname><given-names>J-C</given-names></name>, <name name-style="western"><surname>Kowanetz</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Fine</surname><given-names>GD</given-names></name>, <name name-style="western"><surname>Hamid</surname><given-names>O</given-names></name>, <name name-style="western"><surname>Gordon</surname><given-names>MS</given-names></name>, <name name-style="western"><surname>Sosman</surname><given-names>JA</given-names></name>, <name name-style="western"><surname>McDermott</surname><given-names>DF</given-names></name>, <name name-style="western"><surname>Powderly</surname><given-names>JD</given-names></name>, <name name-style="western"><surname>Gettinger</surname><given-names>SN</given-names></name> et al.</person-group><article-title>Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients</article-title>. <source>Nature</source><year>2014</year>; <volume>515</volume>:<fpage>563</fpage>-<lpage>7</lpage>; PMID:25428504; http://dx.doi.org/<pub-id pub-id-type="doi">10.1038/nature14011</pub-id><pub-id pub-id-type="pmid">25428504</pub-id></mixed-citation></ref><ref id="cit0002"><label>2.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Hodi</surname><given-names>FS</given-names></name>, <name name-style="western"><surname>O'Day</surname><given-names>SJ</given-names></name>, <name name-style="western"><surname>McDermott</surname><given-names>DF</given-names></name>, <name name-style="western"><surname>Weber</surname><given-names>RW</given-names></name>, <name name-style="western"><surname>Sosman</surname><given-names>JA</given-names></name>, <name name-style="western"><surname>Haanen</surname><given-names>JB</given-names></name>, <name name-style="western"><surname>Gonzalez</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Robert</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Schadendorf</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Hassel</surname><given-names>JC</given-names></name> et al.</person-group><article-title>Improved survival with ipilimumab in patients with metastatic melanoma</article-title>. <source>N Engl J Med</source><year>2010</year>; <volume>363</volume>:<fpage>711</fpage>-<lpage>23</lpage>; PMID:20525992; http://dx.doi.org/<pub-id pub-id-type="doi">10.1056/NEJMoa1003466</pub-id><pub-id pub-id-type="pmid">20525992</pub-id></mixed-citation></ref><ref id="cit0003"><label>3.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Le</surname><given-names>DT</given-names></name>, <name name-style="western"><surname>Uram</surname><given-names>JN</given-names></name>, <name name-style="western"><surname>Wang</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Bartlett</surname><given-names>BR</given-names></name>, <name name-style="western"><surname>Kemberling</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Eyring</surname><given-names>AD</given-names></name>, <name name-style="western"><surname>Skora</surname><given-names>AD</given-names></name>, <name name-style="western"><surname>Luber</surname><given-names>BS</given-names></name>, <name name-style="western"><surname>Azad</surname><given-names>NS</given-names></name>, <name name-style="western"><surname>Laheru</surname><given-names>D</given-names></name> et al.</person-group><article-title>PD-1 blockade in tumors with mismatch-repair deficiency</article-title>. <source>N Engl J Med</source><year>2015</year>; <volume>372</volume>:<fpage>2509</fpage>-<lpage>20</lpage>; PMID:26028255; http://dx.doi.org/<pub-id pub-id-type="doi">10.1056/NEJMoa1500596</pub-id><pub-id pub-id-type="pmid">26028255</pub-id></mixed-citation></ref><ref id="cit0004"><label>4.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Powles</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Eder</surname><given-names>JP</given-names></name>, <name name-style="western"><surname>Fine</surname><given-names>GD</given-names></name>, <name name-style="western"><surname>Braiteh</surname><given-names>FS</given-names></name>, <name name-style="western"><surname>Loriot</surname><given-names>Y</given-names></name>, <name name-style="western"><surname>Cruz</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Bellmunt</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Burris</surname><given-names>HA</given-names></name>, <name name-style="western"><surname>Petrylak</surname><given-names>DP</given-names></name>, <name name-style="western"><surname>Teng</surname><given-names>S</given-names></name> et al.</person-group><article-title>MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer</article-title>. <source>Nature</source><year>2014</year>; <volume>515</volume>:<fpage>558</fpage>-<lpage>62</lpage>; PMID:25428503; http://dx.doi.org/<pub-id pub-id-type="doi">10.1038/nature13904</pub-id><pub-id pub-id-type="pmid">25428503</pub-id></mixed-citation></ref><ref id="cit0005"><label>5.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Hamid</surname><given-names>O</given-names></name>, <name name-style="western"><surname>Robert</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Daud</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Hodi</surname><given-names>FS</given-names></name>, <name name-style="western"><surname>Hwu</surname><given-names>W-J</given-names></name>, <name name-style="western"><surname>Kefford</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Wolchok</surname><given-names>JD</given-names></name>, <name name-style="western"><surname>Hersey</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Joseph</surname><given-names>RW</given-names></name>, <name name-style="western"><surname>Weber</surname><given-names>JS</given-names></name> et al.</person-group><article-title>Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma</article-title>. <source>N Engl J Med</source><year>2013</year>; <volume>369</volume>:<fpage>134</fpage>-<lpage>44</lpage>; PMID:23724846; http://dx.doi.org/<pub-id pub-id-type="doi">10.1056/NEJMoa1305133</pub-id><pub-id pub-id-type="pmid">23724846</pub-id></mixed-citation></ref><ref id="cit0006"><label>6.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Borghaei</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Paz-Ares</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Horn</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Spigel</surname><given-names>DR</given-names></name>, <name name-style="western"><surname>Steins</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Ready</surname><given-names>NE</given-names></name>, <name name-style="western"><surname>Chow</surname><given-names>LQ</given-names></name>, <name name-style="western"><surname>Vokes</surname><given-names>EE</given-names></name>, <name name-style="western"><surname>Felip</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Holgado</surname><given-names>E</given-names></name> et al.</person-group><article-title>Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer</article-title>. <source>N Engl J Med</source><year>2015</year>; <volume>373</volume>:<fpage>1627</fpage>-<lpage>39</lpage>; PMID:26412456; http://dx.doi.org/<pub-id pub-id-type="doi">10.1056/NEJMoa1507643</pub-id><pub-id pub-id-type="pmid">26412456</pub-id></mixed-citation></ref><ref id="cit0007"><label>7.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Bouffet</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Larouche</surname><given-names>V</given-names></name>, <name name-style="western"><surname>Campbell</surname><given-names>BB</given-names></name>, <name name-style="western"><surname>Merico</surname><given-names>D</given-names></name>, <name name-style="western"><surname>de Borja</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Aronson</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Durno</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Krueger</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Cabric</surname><given-names>V</given-names></name>, <name name-style="western"><surname>Ramaswamy</surname><given-names>V</given-names></name> et al.</person-group><article-title>Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency</article-title>. <source>J Clin Oncol</source><year>2016</year>; <volume>34</volume>:<fpage>2206</fpage>-<lpage>11</lpage>; PMID:27001570; http://dx.doi.org/<pub-id pub-id-type="doi">10.1200/JCO.2016.66.6552</pub-id><pub-id pub-id-type="pmid">27001570</pub-id></mixed-citation></ref><ref id="cit0008"><label>8.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Brown</surname><given-names>SD</given-names></name>, <name name-style="western"><surname>Warren</surname><given-names>RL</given-names></name>, <name name-style="western"><surname>Gibb</surname><given-names>EA</given-names></name>, <name name-style="western"><surname>Martin</surname><given-names>SD</given-names></name>, <name name-style="western"><surname>Spinelli</surname><given-names>JJ</given-names></name>, <name name-style="western"><surname>Nelson</surname><given-names>BH</given-names></name>, <name name-style="western"><surname>Holt</surname><given-names>RA</given-names></name></person-group><article-title>Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival</article-title>. <source>Genome Res</source><year>2014</year>; <volume>24</volume>:<fpage>743</fpage>-<lpage>50</lpage>; PMID:24782321; http://dx.doi.org/<pub-id pub-id-type="doi">10.1101/gr.165985.113</pub-id><pub-id pub-id-type="pmid">24782321</pub-id></mixed-citation></ref><ref id="cit0009"><label>9.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Rooney</surname><given-names>MS</given-names></name>, <name name-style="western"><surname>Shukla</surname><given-names>SA</given-names></name>, <name name-style="western"><surname>Wu</surname><given-names>CJ</given-names></name>, <name name-style="western"><surname>Getz</surname><given-names>G</given-names></name>, <name name-style="western"><surname>Hacohen</surname><given-names>N</given-names></name></person-group><article-title>Molecular and genetic properties of tumors associated with local immune cytolytic activity</article-title>. <source>Cell</source><year>2015</year>; <volume>160</volume>:<fpage>48</fpage>-<lpage>61</lpage>; PMID:25594174; http://dx.doi.org/<pub-id pub-id-type="doi">10.1016/j.cell.2014.12.033</pub-id><pub-id pub-id-type="pmid">25594174</pub-id></mixed-citation></ref><ref id="cit0010"><label>10.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Giannakis</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Mu</surname><given-names>XJ</given-names></name>, <name name-style="western"><surname>Shukla</surname><given-names>SA</given-names></name>, <name name-style="western"><surname>Qian</surname><given-names>ZR</given-names></name>, <name name-style="western"><surname>Cohen</surname><given-names>O</given-names></name>, <name name-style="western"><surname>Nishihara</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Bahl</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Cao</surname><given-names>Y</given-names></name>, <name name-style="western"><surname>Amin-Mansour</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Yamauchi</surname><given-names>M</given-names></name> et al.</person-group><article-title>Genomic correlates of immune-cell infiltrates in colorectal carcinoma</article-title>. <source>Cell Rep</source><year>2016</year>; <volume>15</volume>:<fpage>857</fpage>-<lpage>65</lpage>; http://dx.doi.org/<pub-id pub-id-type="doi">10.1016/j.celrep.2016.03.075</pub-id></mixed-citation></ref><ref id="cit0011"><label>11.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Pardoll</surname><given-names>DM</given-names></name></person-group><article-title>The blockade of immune checkpoints in cancer immunotherapy</article-title>. <source>Nat Rev Cancer</source><year>2012</year>; <volume>12</volume>:<fpage>252</fpage>-<lpage>64</lpage>; PMID:22437870; http://dx.doi.org/<pub-id pub-id-type="doi">10.1038/nrc3239</pub-id><pub-id pub-id-type="pmid">22437870</pub-id></mixed-citation></ref><ref id="cit0012"><label>12.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Rizvi</surname><given-names>NA</given-names></name>, <name name-style="western"><surname>Hellmann</surname><given-names>MD</given-names></name>, <name name-style="western"><surname>Snyder</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Kvistborg</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Makarov</surname><given-names>V</given-names></name>, <name name-style="western"><surname>Havel</surname><given-names>JJ</given-names></name>, <name name-style="western"><surname>Lee</surname><given-names>W</given-names></name>, <name name-style="western"><surname>Yuan</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Wong</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Ho</surname><given-names>TS</given-names></name> et al.</person-group><article-title>Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer</article-title>. <source>Science</source><year>2015</year>; <volume>348</volume>:<fpage>124</fpage>-<lpage>8</lpage>; http://dx.doi.org/<pub-id pub-id-type="doi">10.1126/science.aaa1348</pub-id><pub-id pub-id-type="pmid">25765070</pub-id></mixed-citation></ref><ref id="cit0013"><label>13.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Snyder</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Makarov</surname><given-names>V</given-names></name>, <name name-style="western"><surname>Merghoub</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Yuan</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Zaretsky</surname><given-names>JM</given-names></name>, <name name-style="western"><surname>Desrichard</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Walsh</surname><given-names>LA</given-names></name>, <name name-style="western"><surname>Postow</surname><given-names>MA</given-names></name>, <name name-style="western"><surname>Wong</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Ho</surname><given-names>TS</given-names></name> et al.</person-group><article-title>Genetic basis for clinical response to CTLA-4 blockade in melanoma</article-title>. <source>N Engl J Med</source><year>2014</year>; <volume>371</volume>:<fpage>2189</fpage>-<lpage>99</lpage>; PMID:25409260; http://dx.doi.org/<pub-id pub-id-type="doi">10.1056/NEJMoa1406498</pub-id><pub-id pub-id-type="pmid">25409260</pub-id></mixed-citation></ref><ref id="cit0014"><label>14.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Chan</surname><given-names>TA</given-names></name>, <name name-style="western"><surname>Wolchok</surname><given-names>JD</given-names></name>, <name name-style="western"><surname>Snyder</surname><given-names>A</given-names></name></person-group><article-title>Genetic basis for clinical response to CTLA-4 blockade in melanoma</article-title>. <source>N Engl J Med</source><year>2015</year>; <volume>373</volume>:<fpage>1984</fpage>-<lpage>1984</lpage>. PMID:26559592; http://dx.doi.org/<pub-id pub-id-type="doi">10.1056/NEJMc1508163</pub-id><pub-id pub-id-type="pmid">26559592</pub-id></mixed-citation></ref><ref id="cit0015"><label>15.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Zou</surname><given-names>W</given-names></name>, <name name-style="western"><surname>Wolchok</surname><given-names>JD</given-names></name>, <name name-style="western"><surname>Chen</surname><given-names>L</given-names></name></person-group><article-title>PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations</article-title>. <source>Sci Transl Med</source><year>2016</year>; <volume>8</volume>:<fpage>328rv4</fpage>; PMID:26936508; http://dx.doi.org/<pub-id pub-id-type="doi">10.1126/scitranslmed.aad7118</pub-id><pub-id pub-id-type="pmid">26936508</pub-id></mixed-citation></ref><ref id="cit0016"><label>16.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Tumeh</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Harview</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Yearley</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Al</surname><given-names>E</given-names></name></person-group><article-title>PD-1 blockade induces responses by inhibiting adaptive immune resistance</article-title>. <source>Nature</source><year>2014</year>; <volume>515</volume>:<fpage>568</fpage>-<lpage>71</lpage>; PMID:25428505; http://dx.doi.org/<pub-id pub-id-type="doi">10.1038/nature13954</pub-id><pub-id pub-id-type="pmid">25428505</pub-id></mixed-citation></ref><ref id="cit0017"><label>17.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Mlecnik</surname><given-names>B</given-names></name>, <name name-style="western"><surname>Bindea</surname><given-names>G</given-names></name>, <name name-style="western"><surname>Angell</surname><given-names>HK</given-names></name>, <name name-style="western"><surname>Maby</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Angelova</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Tougeron</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Church</surname><given-names>SE</given-names></name>, <name name-style="western"><surname>Lafontaine</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Fischer</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Fredriksen</surname><given-names>T</given-names></name> et al.</person-group><article-title>Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability</article-title>. <source>Immunity</source><year>2016</year>; <volume>44</volume>:<fpage>698</fpage>-<lpage>711</lpage>; PMID:26982367; http://dx.doi.org/<pub-id pub-id-type="doi">10.1016/j.immuni.2016.02.025</pub-id><pub-id pub-id-type="pmid">26982367</pub-id></mixed-citation></ref><ref id="cit0018"><label>18.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Becht</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Giraldo</surname><given-names>NA</given-names></name>, <name name-style="western"><surname>Germain</surname><given-names>C</given-names></name>, <name name-style="western"><surname>de Reyniès</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Laurent-Puig</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Zucman-Rossi</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Dieu-Nosjean</surname><given-names>M-C</given-names></name>, <name name-style="western"><surname>Sautès-Fridman</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Fridman</surname><given-names>WH</given-names></name></person-group><article-title>Immune contexture, immunoscore, and malignant cell molecular subgroups for prognostic and theranostic classifications of cancers</article-title>. <year>2016</year>; <volume>130</volume>:<fpage>95</fpage>-<lpage>190</lpage>; PMID:26923001; http://dx.doi.org/23636398<pub-id pub-id-type="doi">10.1016/bs.ai.2015.12.002</pub-id></mixed-citation></ref><ref id="cit0019"><label>19.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><collab>Cancer Genome Atlas Research Network</collab>, <name name-style="western"><surname>Kandoth</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Schultz</surname><given-names>N</given-names></name>, <name name-style="western"><surname>Cherniack</surname><given-names>AD</given-names></name>, <name name-style="western"><surname>Akbani</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Liu</surname><given-names>Y</given-names></name>, <name name-style="western"><surname>Shen</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Robertson</surname><given-names>AG</given-names></name>, <name name-style="western"><surname>Pashtan</surname><given-names>I</given-names></name>, <name name-style="western"><surname>Shen</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Benz</surname><given-names>CC</given-names></name> et al.</person-group><article-title>Integrated genomic characterization of endometrial carcinoma</article-title>. <source>Nature</source><year>2013</year>; <volume>497</volume>:<fpage>67</fpage>-<lpage>73</lpage>; PMID:23636398; http://dx.doi.org/<pub-id pub-id-type="doi">10.1038/nature12113</pub-id><pub-id pub-id-type="pmid">23636398</pub-id></mixed-citation></ref><ref id="cit0020"><label>20.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>van Gool</surname><given-names>IC</given-names></name>, <name name-style="western"><surname>Eggink</surname><given-names>FA</given-names></name>, <name name-style="western"><surname>Freeman-Mills</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Stelloo</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Marchi</surname><given-names>E</given-names></name>, <name name-style="western"><surname>de Bruyn</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Palles</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Nout</surname><given-names>RA</given-names></name>, <name name-style="western"><surname>de Kroon</surname><given-names>CD</given-names></name>, <name name-style="western"><surname>Osse</surname><given-names>EM</given-names></name> et al.</person-group><article-title>POLE proofreading mutations elicit an anti-tumor immune response in endometrial cancer</article-title>. <source>Clin Cancer Res</source><year>2015</year>; <volume>21</volume>:<fpage>3347</fpage>-<lpage>56</lpage>; PMID:25878334; http://dx.doi.org/<pub-id pub-id-type="doi">10.1158/1078-0432.CCR-15-0057</pub-id><pub-id pub-id-type="pmid">25878334</pub-id></mixed-citation></ref><ref id="cit0021"><label>21.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Howitt</surname><given-names>BE</given-names></name>, <name name-style="western"><surname>Shukla</surname><given-names>SA</given-names></name>, <name name-style="western"><surname>Sholl</surname><given-names>LM</given-names></name>, <name name-style="western"><surname>Ritterhouse</surname><given-names>LL</given-names></name>, <name name-style="western"><surname>Watkins</surname><given-names>JC</given-names></name>, <name name-style="western"><surname>Rodig</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Stover</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Strickland</surname><given-names>KC</given-names></name>, <name name-style="western"><surname>D'Andrea</surname><given-names>AD</given-names></name>, <name name-style="western"><surname>Wu</surname><given-names>CJ</given-names></name> et al.</person-group><article-title>Association of polymerase e–mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1</article-title>. <source>JAMA Oncol</source><year>2015</year>; 1:1319–23; PMID:26181000; http://dx.doi.org/27141333<pub-id pub-id-type="doi">10.1001/jamaoncol.2015.2151</pub-id></mixed-citation></ref><ref id="cit0022"><label>22.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Bellone</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Centritto</surname><given-names>F</given-names></name>, <name name-style="western"><surname>Black</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Schwab</surname><given-names>C</given-names></name>, <name name-style="western"><surname>English</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Cocco</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Lopez</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Bonazzoli</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Predolini</surname><given-names>F</given-names></name>, <name name-style="western"><surname>Ferrari</surname><given-names>F</given-names></name> et al.</person-group><article-title>Polymerase ε (POLE) ultra-mutated tumors induce robust tumor-specific CD4+ T cell responses in endometrial cancer patients</article-title>. <source>Gynecol Oncol</source><year>2015</year>; <volume>138</volume>:<fpage>11</fpage>-<lpage>7</lpage>; PMID:25931171; http://dx.doi.org/27141333<pub-id pub-id-type="doi">10.1016/j.ygyno.2015.04.027</pub-id><pub-id pub-id-type="pmid">25931171</pub-id></mixed-citation></ref><ref id="cit0023"><label>23.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>van Gool</surname><given-names>IC</given-names></name>, <name name-style="western"><surname>Bosse</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Church</surname><given-names>DN</given-names></name></person-group><article-title>POLE proofreading mutation, immune response and prognosis in endometrial cancer</article-title>. <source>Oncoimmunology</source><year>2016</year>; <volume>5</volume>:<fpage>e1072675</fpage>; PMID:27141333; http://dx.doi.org/<pub-id pub-id-type="doi">10.1080/2162402X.2015.1072675</pub-id><pub-id pub-id-type="pmid">27141333</pub-id></mixed-citation></ref><ref id="cit0024"><label>24.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Gros</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Parkhurst</surname><given-names>MR</given-names></name>, <name name-style="western"><surname>Tran</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Pasetto</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Robbins</surname><given-names>PF</given-names></name>, <name name-style="western"><surname>Ilyas</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Prickett</surname><given-names>TD</given-names></name>, <name name-style="western"><surname>Gartner</surname><given-names>JJ</given-names></name>, <name name-style="western"><surname>Crystal</surname><given-names>JS</given-names></name>, <name name-style="western"><surname>Roberts</surname><given-names>IM</given-names></name> et al.</person-group><article-title>Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients</article-title>. <source>Nat Med</source><year>2016</year>; <volume>22</volume>:<fpage>433</fpage>-<lpage>8</lpage>; PMID:26901407; http://dx.doi.org/<pub-id pub-id-type="doi">10.1038/nm.4051</pub-id><pub-id pub-id-type="pmid">26901407</pub-id></mixed-citation></ref><ref id="cit0025"><label>25.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Mehnert</surname><given-names>JM</given-names></name>, <name name-style="western"><surname>Panda</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Zhong</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Hirshfield</surname><given-names>K</given-names></name>, <name name-style="western"><surname>Damare</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Lane</surname><given-names>K</given-names></name>, <name name-style="western"><surname>Sokol</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Stein</surname><given-names>MN</given-names></name>, <name name-style="western"><surname>Rodriguez-rodriquez</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Kaufman</surname><given-names>HL</given-names></name> et al.</person-group><article-title>Immune activation and response to pembrolizumab in POLE -mutant endometrial cancer</article-title>. <source>JCI</source><year>2016</year>; <volume>126</volume>:<fpage>1</fpage>-<lpage>7</lpage>; PMID:27159395; http://dx.doi.org/12091876<pub-id pub-id-type="doi">10.1172/JCI84940</pub-id></mixed-citation></ref><ref id="cit0026"><label>26.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Santin</surname><given-names>AD</given-names></name>, <name name-style="western"><surname>Bellone</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Buza</surname><given-names>N</given-names></name>, <name name-style="western"><surname>Choi</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Schwartz</surname><given-names>PE</given-names></name>, <name name-style="western"><surname>Schlessinger</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Lifton</surname><given-names>RP</given-names></name></person-group><article-title>Regression of chemotherapy-resistant Polymerase epsilon (POLE) ultra-mutated and MSH6 hyper-mutated endometrial tumors with nivolumab</article-title>. <source>Clin Cancer Res</source><year>2016</year>; 22:5682-5687; PMID:27486176; http://dx.doi.org/12091876<pub-id pub-id-type="doi">10.1158/1078-0432.CCR-16-1031</pub-id></mixed-citation></ref><ref id="cit0027"><label>27.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Dong</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Strome</surname><given-names>SE</given-names></name>, <name name-style="western"><surname>Salomao</surname><given-names>DR</given-names></name>, <name name-style="western"><surname>Tamura</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Hirano</surname><given-names>F</given-names></name>, <name name-style="western"><surname>Flies</surname><given-names>DB</given-names></name>, <name name-style="western"><surname>Roche</surname><given-names>PC</given-names></name>, <name name-style="western"><surname>Lu</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Zhu</surname><given-names>G</given-names></name>, <name name-style="western"><surname>Tamada</surname><given-names>K</given-names></name> et al.</person-group><article-title>Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion</article-title>. <source>Nat Med</source><year>2002</year>; <volume>8</volume>:<fpage>793</fpage>-<lpage>800</lpage>; PMID:12091876; http://dx.doi.org/<pub-id pub-id-type="doi">10.1038/nm0902-1039c</pub-id><pub-id pub-id-type="pmid">12091876</pub-id></mixed-citation></ref><ref id="cit0028"><label>28.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Heeren</surname><given-names>AM</given-names></name>, <name name-style="western"><surname>Koster</surname><given-names>BD</given-names></name>, <name name-style="western"><surname>Samuels</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Ferns</surname><given-names>DM</given-names></name>, <name name-style="western"><surname>Chondronasiou</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Kenter</surname><given-names>GG</given-names></name>, <name name-style="western"><surname>Jordanova</surname><given-names>ES</given-names></name>, <name name-style="western"><surname>de Gruijl</surname><given-names>TD</given-names></name></person-group><article-title>High and interrelated rates of PD-L1+CD14+ antigen-presenting cells and regulatory T cells mark the microenvironment of metastatic lymph nodes from patients with cervical cancer</article-title>. <source>Cancer Immunol Res</source><year>2015</year>; <volume>3</volume>:<fpage>48</fpage>-<lpage>58</lpage>; PMID:25361854; http://dx.doi.org/<pub-id pub-id-type="doi">10.1158/2326-6066.CIR-14-0149</pub-id><pub-id pub-id-type="pmid">25361854</pub-id></mixed-citation></ref><ref id="cit0029"><label>29.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Schultheis</surname><given-names>AM</given-names></name>, <name name-style="western"><surname>Scheel</surname><given-names>AH</given-names></name>, <name name-style="western"><surname>Ozretić</surname><given-names>L</given-names></name>, <name name-style="western"><surname>George</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Thomas</surname><given-names>RK</given-names></name>, <name name-style="western"><surname>Hagemann</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Zander</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Wolf</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Buettner</surname><given-names>R</given-names></name></person-group><article-title>PD-L1 expression in small cell neuroendocrine carcinomas</article-title>. <source>Eur J Cancer</source><year>2015</year>; <volume>51</volume>:<fpage>421</fpage>-<lpage>6</lpage>; PMID:25582496; http://dx.doi.org/<pub-id pub-id-type="doi">10.1016/j.ejca.2014.12.006</pub-id><pub-id pub-id-type="pmid">25582496</pub-id></mixed-citation></ref><ref id="cit0030"><label>30.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Curiel</surname><given-names>TJ</given-names></name>, <name name-style="western"><surname>Wei</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Dong</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Alvarez</surname><given-names>X</given-names></name>, <name name-style="western"><surname>Cheng</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Mottram</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Krzysiek</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Knutson</surname><given-names>KL</given-names></name>, <name name-style="western"><surname>Daniel</surname><given-names>B</given-names></name>, <name name-style="western"><surname>Zimmermann</surname><given-names>MC</given-names></name> et al.</person-group><article-title>Blockade of B7-H1 improves myeloid dendritic cell–mediated antitumor immunity</article-title>. <source>Nat Med</source><year>2003</year>; <volume>9</volume>:<fpage>562</fpage>-<lpage>7</lpage>; PMID:12704383; http://dx.doi.org/<pub-id pub-id-type="doi">10.1038/nm863</pub-id><pub-id pub-id-type="pmid">12704383</pub-id></mixed-citation></ref><ref id="cit0031"><label>31.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Bakhsh</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Kinloch</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Hoang</surname><given-names>LN</given-names></name>, <name name-style="western"><surname>Soslow</surname><given-names>RA</given-names></name>, <name name-style="western"><surname>Köbel</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Lee</surname><given-names>CH</given-names></name>, <name name-style="western"><surname>Mcalpine</surname><given-names>JN</given-names></name>, <name name-style="western"><surname>Mcconechy</surname><given-names>MK</given-names></name>, <name name-style="western"><surname>Gilks</surname><given-names>CB</given-names></name></person-group><article-title>Histopathological features of endometrial carcinomas associated with POLE mutations: Implications for decisions about adjuvant therapy</article-title>. <source>Histopathology</source><year>2015</year>; <volume>68</volume>:<fpage>916</fpage>-<lpage>24</lpage>; PMID:26416160; http://dx.doi.org/<pub-id pub-id-type="doi">10.1111/his.12878</pub-id><pub-id pub-id-type="pmid">26416160</pub-id></mixed-citation></ref><ref id="cit0032"><label>32.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>McLaughlin</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Han</surname><given-names>G</given-names></name>, <name name-style="western"><surname>Schalper</surname><given-names>KA</given-names></name>, <name name-style="western"><surname>Carvajal-Hausdorf</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Pelekanou</surname><given-names>V</given-names></name>, <name name-style="western"><surname>Rehman</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Velcheti</surname><given-names>V</given-names></name>, <name name-style="western"><surname>Herbst</surname><given-names>R</given-names></name>, <name name-style="western"><surname>LoRusso</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Rimm</surname><given-names>DL</given-names></name> et al.</person-group><article-title>Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer</article-title>. <source>JAMA Oncol</source><year>2016</year>; <volume>2</volume>:<fpage>46</fpage>; PMID:26562159; http://dx.doi.org/<pub-id pub-id-type="doi">10.1001/jamaoncol.2015.3638</pub-id><pub-id pub-id-type="pmid">26562159</pub-id></mixed-citation></ref><ref id="cit0033"><label>33.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Dieu-Nosjean</surname><given-names>MC</given-names></name>, <name name-style="western"><surname>Giraldo</surname><given-names>NA</given-names></name>, <name name-style="western"><surname>Kaplon</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Germain</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Fridman</surname><given-names>WH</given-names></name>, <name name-style="western"><surname>Sautès-Fridman</surname><given-names>C</given-names></name></person-group><article-title>Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers</article-title>. <source>Immunol Rev</source><year>2016</year>; <volume>271</volume>:<fpage>260</fpage>-<lpage>75</lpage>; PMID:27088920; http://dx.doi.org/<pub-id pub-id-type="doi">10.1111/imr.12405</pub-id><pub-id pub-id-type="pmid">27088920</pub-id></mixed-citation></ref><ref id="cit0034"><label>34.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Germain</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Gnjatic</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Dieu-Nosjean</surname><given-names>MC</given-names></name></person-group><article-title>Tertiary lymphoid structure-associated B cells are key players in anti-tumor immunity</article-title>. <source>Front Immun</source><year>2015</year>; <volume>6</volume>:<fpage>1</fpage>-<lpage>14</lpage>; PMID:25657648; http://dx.doi.org/<pub-id pub-id-type="doi">10.3389/fimmu.2015.00067</pub-id><pub-id pub-id-type="pmid">25657648</pub-id></mixed-citation></ref><ref id="cit0035"><label>35.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Kroeger</surname><given-names>DR</given-names></name>, <name name-style="western"><surname>Milne</surname><given-names>K</given-names></name>, <name name-style="western"><surname>Nelson</surname><given-names>BH</given-names></name></person-group><article-title>Tumor-infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T-cell responses, and superior prognosis in ovarian cancer</article-title>. <source>Clin Cancer Res</source><year>2016</year>; <volume>22</volume>:<fpage>3005</fpage>-<lpage>15</lpage>; PMID:26763251; http://dx.doi.org/<pub-id pub-id-type="doi">10.1158/1078-0432.CCR-15-2762</pub-id><pub-id pub-id-type="pmid">26763251</pub-id></mixed-citation></ref><ref id="cit0036"><label>36.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Zhang</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Liu</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Zhang</surname><given-names>Z</given-names></name>, <name name-style="western"><surname>Chan</surname><given-names>DW</given-names></name>, <name name-style="western"><surname>Rodland</surname><given-names>KD</given-names></name>, <name name-style="western"><surname>Zhang</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Liu</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Zhang</surname><given-names>Z</given-names></name>, <name name-style="western"><surname>Payne</surname><given-names>SH</given-names></name>, <name name-style="western"><surname>Zhang</surname><given-names>B</given-names></name> et al.</person-group><article-title>Integrated proteogenomic characterization of human high-grade serous ovarian cancer resource integrated proteogenomic characterization of human high-grade serous ovarian cancer</article-title> Cell 2016; 166:755-65; PMID:27372738; http://dx.doi.org/24714771<pub-id pub-id-type="doi">10.1016/j.cell.2016.05.069</pub-id></mixed-citation></ref><ref id="cit0037"><label>37.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Stelloo</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Versluis</surname><given-names>MA</given-names></name>, <name name-style="western"><surname>Nijman</surname><given-names>HW</given-names></name>, <name name-style="western"><surname>de Bruyn</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Plat</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Osse</surname><given-names>EM</given-names></name>, <name name-style="western"><surname>van Dijk</surname><given-names>RH</given-names></name>, <name name-style="western"><surname>Nout</surname><given-names>RA</given-names></name>, <name name-style="western"><surname>Creutzberg</surname><given-names>CL</given-names></name>, <name name-style="western"><surname>de Bock</surname><given-names>GH</given-names></name> et al.</person-group><article-title>Microsatellite instability derived <italic>JAK1</italic> frameshift mutations are associated with tumor immune evasion in endometrioid endometrial cancer</article-title>. <source>Oncotarget</source><year>2016</year>; 7:39885-39893; PMID:27213585; http://dx.doi.org/24714771<pub-id pub-id-type="doi">10.18632/oncotarget.9414</pub-id></mixed-citation></ref><ref id="cit0038"><label>38.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Taube</surname><given-names>JM</given-names></name>, <name name-style="western"><surname>Klein</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Brahmer</surname><given-names>JR</given-names></name>, <name name-style="western"><surname>Xu</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Pan</surname><given-names>X</given-names></name>, <name name-style="western"><surname>Kim</surname><given-names>JH</given-names></name>, <name name-style="western"><surname>Chen</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Pardoll</surname><given-names>DM</given-names></name>, <name name-style="western"><surname>Topalian</surname><given-names>SL</given-names></name>, <name name-style="western"><surname>Anders</surname><given-names>RA</given-names></name></person-group><article-title>Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy</article-title>. <source>Clin Cancer Res</source><year>2014</year>; <volume>20</volume>:<fpage>5064</fpage>-<lpage>74</lpage>; PMID:24714771; http://dx.doi.org/<pub-id pub-id-type="doi">10.1158/1078-0432.CCR-13-3271</pub-id><pub-id pub-id-type="pmid">24714771</pub-id></mixed-citation></ref><ref id="cit0039"><label>39.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Billingsley</surname><given-names>CC</given-names></name>, <name name-style="western"><surname>Cohn</surname><given-names>DE</given-names></name>, <name name-style="western"><surname>Mutch</surname><given-names>DG</given-names></name>, <name name-style="western"><surname>Hade</surname><given-names>EM</given-names></name>, <name name-style="western"><surname>Goodfellow</surname><given-names>PJ</given-names></name></person-group><article-title>Prognostic significance of POLE exonuclease domain mutations in high-grade endometrioid endometrial cancer on survival and recurrence</article-title>. <source>Int J Gynecol Cancer</source><year>2016</year>; 26:933-8; PMID:26937754; http://dx.doi.org/25505230<pub-id pub-id-type="doi">10.1097/IGC.0000000000000681</pub-id></mixed-citation></ref><ref id="cit0040"><label>40.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Church</surname><given-names>DN</given-names></name>, <name name-style="western"><surname>Stelloo</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Nout</surname><given-names>RA</given-names></name>, <name name-style="western"><surname>Valtcheva</surname><given-names>N</given-names></name>, <name name-style="western"><surname>Depreeuw</surname><given-names>J</given-names></name>, <name name-style="western"><surname>ter Haar</surname><given-names>N</given-names></name>, <name name-style="western"><surname>Noske</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Amant</surname><given-names>F</given-names></name>, <name name-style="western"><surname>Tomlinson</surname><given-names>IP</given-names></name>, <name name-style="western"><surname>Wild</surname><given-names>PJ</given-names></name> et al.</person-group><article-title>Prognostic significance of POLE proofreading mutations in endometrial cancer</article-title>. <source>JNCI J Natl Cancer Inst</source><year>2014</year>; <volume>107</volume>:<fpage>dju402</fpage>; PMID:25505230; http://dx.doi.org/<pub-id pub-id-type="doi">10.1093/jnci/dju402</pub-id><pub-id pub-id-type="pmid">25505230</pub-id></mixed-citation></ref><ref id="cit0041"><label>41.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>McConechy</surname><given-names>MK</given-names></name>, <name name-style="western"><surname>Talhouk</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Leung</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Chiu</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Yang</surname><given-names>W</given-names></name>, <name name-style="western"><surname>Senz</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Reha-Krantz</surname><given-names>LJ</given-names></name>, <name name-style="western"><surname>Lee</surname><given-names>C-H</given-names></name>, <name name-style="western"><surname>Huntsman</surname><given-names>DG</given-names></name>, <name name-style="western"><surname>Gilks</surname><given-names>CB</given-names></name> et al.</person-group><article-title>Endometrial carcinomas with POLE exonuclease domain mutations have a favorable prognosis</article-title>. <source>Clin Cancer Res</source><year>2016</year>; 22:2865-73; PMID:26763250; http://dx.doi.org/25720322<pub-id pub-id-type="doi">10.1158/1078-0432.CCR-15-2233</pub-id></mixed-citation></ref><ref id="cit0042"><label>42.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Stelloo</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Bosse</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Nout</surname><given-names>RA</given-names></name>, <name name-style="western"><surname>MacKay</surname><given-names>HJ</given-names></name>, <name name-style="western"><surname>Church</surname><given-names>DN</given-names></name>, <name name-style="western"><surname>Nijman</surname><given-names>HW</given-names></name>, <name name-style="western"><surname>Leary</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Edmondson</surname><given-names>RJ</given-names></name>, <name name-style="western"><surname>Powell</surname><given-names>ME</given-names></name>, <name name-style="western"><surname>Crosbie</surname><given-names>EJ</given-names></name> et al.</person-group><article-title>Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative</article-title>. <source>Mod Pathol</source><year>2015</year>; <volume>28</volume>:<fpage>836</fpage>-<lpage>44</lpage>; PMID:25720322; http://dx.doi.org/<pub-id pub-id-type="doi">10.1038/modpathol.2015.43</pub-id><pub-id pub-id-type="pmid">25720322</pub-id></mixed-citation></ref><ref id="cit0043"><label>43.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Church</surname><given-names>DN</given-names></name>, <name name-style="western"><surname>Briggs</surname><given-names>SEW</given-names></name>, <name name-style="western"><surname>Palles</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Domingo</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Kearsey</surname><given-names>SJ</given-names></name>, <name name-style="western"><surname>Grimes</surname><given-names>JM</given-names></name>, <name name-style="western"><surname>Gorman</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Martin</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Howarth</surname><given-names>KM</given-names></name>, <name name-style="western"><surname>Hodgson</surname><given-names>S V</given-names></name> et al.</person-group><article-title>DNA polymerase ε and δ exonuclease domain mutations in endometrial cancer</article-title>. <source>Hum Mol Genet</source><year>2013</year>; <volume>22</volume>:<fpage>2820</fpage>-<lpage>8</lpage>; PMID:23528559; http://dx.doi.org/<pub-id pub-id-type="doi">10.1093/hmg/ddt131</pub-id><pub-id pub-id-type="pmid">23528559</pub-id></mixed-citation></ref><ref id="cit0044"><label>44.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><collab>The Cancer Genome Atlas Network</collab></person-group><article-title>Comprehensive molecular characterization of human colon and rectal cancer</article-title>. <source>Nature</source><year>2012</year>; 487:330-7; PMID:22810696; http://dx.doi.org/23945592<pub-id pub-id-type="doi">10.1038/nature11252</pub-id></mixed-citation></ref><ref id="cit0045"><label>45.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Alexandrov</surname><given-names>LB</given-names></name>, <name name-style="western"><surname>Nik-Zainal</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Wedge</surname><given-names>DC</given-names></name>, <name name-style="western"><surname>Aparicio</surname><given-names>SA</given-names></name>, <name name-style="western"><surname>Behjati</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Biankin</surname><given-names>A V</given-names></name>, <name name-style="western"><surname>Bignell</surname><given-names>GR</given-names></name>, <name name-style="western"><surname>Bolli</surname><given-names>N</given-names></name>, <name name-style="western"><surname>Borg</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Børresen-Dale</surname><given-names>A-L</given-names></name> et al.</person-group><article-title>Signatures of mutational processes in human cancer</article-title>. <source>Nature</source><year>2013</year>; <volume>500</volume>:<fpage>415</fpage>-<lpage>21</lpage>; PMID:23945592; http://dx.doi.org/<pub-id pub-id-type="doi">10.1038/nature12477</pub-id><pub-id pub-id-type="pmid">23945592</pub-id></mixed-citation></ref><ref id="cit0046"><label>46.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Shinbrot</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Henninger</surname><given-names>EE</given-names></name>, <name name-style="western"><surname>Weinhold</surname><given-names>N</given-names></name>, <name name-style="western"><surname>Covington</surname><given-names>KR</given-names></name>, <name name-style="western"><surname>Göksenin</surname><given-names>AY</given-names></name>, <name name-style="western"><surname>Schultz</surname><given-names>N</given-names></name>, <name name-style="western"><surname>Chao</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Doddapaneni</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Muzny</surname><given-names>DM</given-names></name>, <name name-style="western"><surname>Gibbs</surname><given-names>RA</given-names></name> et al.</person-group><article-title>Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication</article-title>. <source>Genome Res</source><year>2014</year>; <volume>24</volume>:<fpage>1740</fpage>-<lpage>50</lpage>; PMID:25228659; http://dx.doi.org/<pub-id pub-id-type="doi">10.1101/gr.174789.114</pub-id><pub-id pub-id-type="pmid">25228659</pub-id></mixed-citation></ref><ref id="cit0047"><label>47.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Erson-Omay</surname><given-names>EZ</given-names></name>, <name name-style="western"><surname>Çağlayan</surname><given-names>AO</given-names></name>, <name name-style="western"><surname>Schultz</surname><given-names>N</given-names></name>, <name name-style="western"><surname>Weinhold</surname><given-names>N</given-names></name>, <name name-style="western"><surname>Omay</surname><given-names>SB</given-names></name>, <name name-style="western"><surname>Özduman</surname><given-names>K</given-names></name>, <name name-style="western"><surname>Köksal</surname><given-names>Y</given-names></name>, <name name-style="western"><surname>Li</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Serin Harmancı</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Clark</surname><given-names>V</given-names></name> et al.</person-group><article-title>Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis</article-title>. <source>Neuro Oncol</source><year>2015</year>; <volume>17</volume>:<fpage>1356</fpage>-<lpage>64</lpage>; PMID:25740784; http://dx.doi.org/<pub-id pub-id-type="doi">10.1093/neuonc/nov027</pub-id><pub-id pub-id-type="pmid">25740784</pub-id></mixed-citation></ref><ref id="cit0048"><label>48.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Rayner</surname><given-names>E</given-names></name>, <name name-style="western"><surname>van Gool</surname><given-names>IC</given-names></name>, <name name-style="western"><surname>Palles</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Kearsey</surname><given-names>SE</given-names></name>, <name name-style="western"><surname>Bosse</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Tomlinson</surname><given-names>I</given-names></name>, <name name-style="western"><surname>Church</surname><given-names>DN</given-names></name></person-group><article-title>A panoply of errors: polymerase proofreading domain mutations in cancer</article-title>. <source>Nat Rev Cancer</source><year>2016</year>; <volume>16</volume>:<fpage>71</fpage>-<lpage>81</lpage>; PMID:26822575; http://dx.doi.org/<pub-id pub-id-type="doi">10.1038/nrc.2015.12</pub-id><pub-id pub-id-type="pmid">26822575</pub-id></mixed-citation></ref><ref id="cit0049"><label>49.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Domingo</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Freeman-Mills</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Rayner</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Glaire</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Briggs</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Vermeulen</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Fessler</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Medema</surname><given-names>JP</given-names></name>, <name name-style="western"><surname>Boot</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Morreau</surname><given-names>H</given-names></name> et al.</person-group><article-title>Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study</article-title>. <source>Lancet Gastroenterol Hepatol</source><year>2016</year>; <volume>1</volume>:<fpage>207</fpage>-<lpage>16</lpage>; http://dx.doi.org/<pub-id pub-id-type="doi">10.1016/S2468-1253(16)30014-0</pub-id><pub-id pub-id-type="pmid">28404093</pub-id></mixed-citation></ref><ref id="cit0050"><label>50.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Gargiulo</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Della Pepa</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Berardi</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Califano</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Scala</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Buonaguro</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Ciliberto</surname><given-names>G</given-names></name>, <name name-style="western"><surname>Brauchli</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Pignata</surname><given-names>S</given-names></name></person-group><article-title>Tumor genotype and immune microenvironment in POLE-ultramutated and MSI-hypermutated Endometrial Cancers: New candidates for checkpoint blockade immunotherapy?</article-title><source>Cancer Treat Rev</source><year>2016</year>; <volume>48</volume>:<fpage>61</fpage>-<lpage>8</lpage>; PMID:27362548; http://dx.doi.org/<pub-id pub-id-type="doi">10.1016/j.ctrv.2016.06.008</pub-id><pub-id pub-id-type="pmid">27362548</pub-id></mixed-citation></ref><ref id="cit0051"><label>51.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>De Boer</surname><given-names>SM</given-names></name>, <name name-style="western"><surname>Powell</surname><given-names>ME</given-names></name>, <name name-style="western"><surname>Mileshkin</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Katsaros</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Bessette</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Haie-meder</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Ottevanger</surname><given-names>PB</given-names></name>, <name name-style="western"><surname>Ledermann</surname><given-names>JA</given-names></name>, <name name-style="western"><surname>Khaw</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Colombo</surname><given-names>A</given-names></name> et al.</person-group><article-title>Toxicity and quality of life after adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk randomised, phase 3 trial</article-title>. <source>Lancet Oncol</source><year>2016</year>; <volume>17</volume>:<fpage>1</fpage>-<lpage>13</lpage>; PMID:26758748; http://dx.doi.org/<pub-id pub-id-type="doi">10.1016/S1470-2045(15)00568-9</pub-id><pub-id pub-id-type="pmid">26758748</pub-id></mixed-citation></ref><ref id="cit0052"><label>52.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>van Eijk</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Stevens</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Morreau</surname><given-names>H</given-names></name>, <name name-style="western"><surname>van Wezel</surname><given-names>T</given-names></name></person-group><article-title>Assessment of a fully automated high-throughput DNA extraction method from formalin-fixed, paraffin-embedded tissue for KRAS, and BRAF somatic mutation analysis</article-title>. <source>Exp Mol Pathol</source><year>2013</year>; <volume>94</volume>:<fpage>121</fpage>-<lpage>5</lpage>; PMID:22750048; http://dx.doi.org/<pub-id pub-id-type="doi">10.1016/j.yexmp.2012.06.004</pub-id><pub-id pub-id-type="pmid">22750048</pub-id></mixed-citation></ref><ref id="cit0053"><label>53.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Van Gool</surname><given-names>IC</given-names></name>, <name name-style="western"><surname>Stelloo</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Nout</surname><given-names>RA</given-names></name>, <name name-style="western"><surname>Nijman</surname><given-names>HW</given-names></name>, <name name-style="western"><surname>Edmondson</surname><given-names>RJ</given-names></name>, <name name-style="western"><surname>Church</surname><given-names>DN</given-names></name>, <name name-style="western"><surname>MacKay</surname><given-names>HJ</given-names></name>, <name name-style="western"><surname>Leary</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Powell</surname><given-names>ME</given-names></name>, <name name-style="western"><surname>Mileshkin</surname><given-names>L</given-names></name> et al.</person-group><article-title>Prognostic significance of L1CAM expression and its association with mutant p53 expression in high-risk endometrial cancer</article-title>. <source>Mod Pathol</source><year>2016</year>; <volume>29</volume>:<fpage>174</fpage>-<lpage>81</lpage>; PMID:26743472; http://dx.doi.org/<pub-id pub-id-type="doi">10.1038/modpathol.2015.147</pub-id><pub-id pub-id-type="pmid">26743472</pub-id></mixed-citation></ref><ref id="cit0054"><label>54.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Workel</surname><given-names>HH</given-names></name>, <name name-style="western"><surname>Komdeur</surname><given-names>FL</given-names></name>, <name name-style="western"><surname>Wouters</surname><given-names>MCA</given-names></name>, <name name-style="western"><surname>Plat</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Klip</surname><given-names>HG</given-names></name>, <name name-style="western"><surname>Eggink</surname><given-names>FA</given-names></name>, <name name-style="western"><surname>Wisman</surname><given-names>GBA</given-names></name>, <name name-style="western"><surname>Arts</surname><given-names>HJG</given-names></name>, <name name-style="western"><surname>Oonk</surname><given-names>MHM</given-names></name>, <name name-style="western"><surname>Mourits</surname><given-names>MJE</given-names></name> et al.</person-group><article-title>CD103 defines intraepithelial CD8+ PD1+ tumour-infiltrating lymphocytes of prognostic significance in endometrial adenocarcinoma</article-title>. <source>Eur J Cancer</source><year>2016</year>; <volume>60</volume>:<fpage>1</fpage>-<lpage>11</lpage>. Available from: <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/pubmed/27038842">http://www.ncbi.nlm.nih.gov/pubmed/27038842</ext-link>; PMID:27038842; http://dx.doi.org/<pub-id pub-id-type="doi">10.1016/j.ejca.2016.02.026</pub-id><pub-id pub-id-type="pmid">27038842</pub-id></mixed-citation></ref><ref id="cit0055"><label>55.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Jordanova</surname><given-names>ES</given-names></name>, <name name-style="western"><surname>Gorter</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Ayachi</surname><given-names>O</given-names></name>, <name name-style="western"><surname>Prins</surname><given-names>F</given-names></name>, <name name-style="western"><surname>Durrant</surname><given-names>LG</given-names></name>, <name name-style="western"><surname>Kenter</surname><given-names>GG</given-names></name>, <name name-style="western"><surname>van der Burg</surname><given-names>SH</given-names></name>, <name name-style="western"><surname>Fleuren</surname><given-names>GJ</given-names></name></person-group><article-title>Human leukocyte antigen class I, MHC class I chain-related molecule A, and CD8+/regulatory T-cell ratio: which variable determines survival of cervical cancer patients?</article-title><source>Clin Cancer Res</source><year>2008</year>; <volume>14</volume>:<fpage>2028</fpage>-<lpage>35</lpage>; PMID:18381941; http://dx.doi.org/<pub-id pub-id-type="doi">10.1158/1078-0432.CCR-07-4554</pub-id><pub-id pub-id-type="pmid">18381941</pub-id></mixed-citation></ref><ref id="cit0056"><label>56.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Nielsen</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Lundegaard</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Blicher</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Lamberth</surname><given-names>K</given-names></name>, <name name-style="western"><surname>Harndahl</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Justesen</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Røder</surname><given-names>G</given-names></name>, <name name-style="western"><surname>Peters</surname><given-names>B</given-names></name>, <name name-style="western"><surname>Sette</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Lund</surname><given-names>O</given-names></name> et al.</person-group><article-title>NetMHCpan, a method for quantitative predictions of peptide binding to any HLA-A and -B locus protein of known sequence</article-title>. <source>PLoS One</source><year>2007</year>; <volume>2</volume>:<fpage>e796</fpage>; PMID:17726526; http://dx.doi.org/23243591<pub-id pub-id-type="doi">10.1371/journal.pone.0000796</pub-id><pub-id pub-id-type="pmid">17726526</pub-id></mixed-citation></ref><ref id="cit0057"><label>57.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Khalili</surname><given-names>JS</given-names></name>, <name name-style="western"><surname>Hanson</surname><given-names>RW</given-names></name>, <name name-style="western"><surname>Szallasi</surname><given-names>Z</given-names></name></person-group><article-title>In silico prediction of tumor antigens derived from functional missense mutations of the cancer gene census</article-title>. <source>Oncoimmunology</source><year>2012</year>; <volume>1</volume>:<fpage>1281</fpage>-<lpage>9</lpage>; PMID:23243591; http://dx.doi.org/<pub-id pub-id-type="doi">10.4161/onci.21511</pub-id><pub-id pub-id-type="pmid">23243591</pub-id></mixed-citation></ref><ref id="cit0058"><label>58.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Duan</surname><given-names>F</given-names></name>, <name name-style="western"><surname>Duitama</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Al Seesi</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Ayres</surname><given-names>CM</given-names></name>, <name name-style="western"><surname>Corcelli</surname><given-names>SA</given-names></name>, <name name-style="western"><surname>Pawashe</surname><given-names>AP</given-names></name>, <name name-style="western"><surname>Blanchard</surname><given-names>T</given-names></name>, <name name-style="western"><surname>McMahon</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Sidney</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Sette</surname><given-names>A</given-names></name> et al.</person-group><article-title>Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity</article-title>. <source>J Exp Med</source><year>2014</year>; <volume>211</volume>:<fpage>2231</fpage>-<lpage>48</lpage>; PMID:25245761; http://dx.doi.org/<pub-id pub-id-type="doi">10.1084/jem.20141308</pub-id><pub-id pub-id-type="pmid">25245761</pub-id></mixed-citation></ref><ref id="cit0059"><label>59.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>van Rooij</surname><given-names>N</given-names></name>, <name name-style="western"><surname>van Buuren</surname><given-names>MM</given-names></name>, <name name-style="western"><surname>Philips</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Velds</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Toebes</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Heemskerk</surname><given-names>B</given-names></name>, <name name-style="western"><surname>van Dijk</surname><given-names>LJA</given-names></name>, <name name-style="western"><surname>Behjati</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Hilkmann</surname><given-names>H</given-names></name>, <name name-style="western"><surname>El Atmioui</surname><given-names>D</given-names></name> et al.</person-group><article-title>Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma</article-title>. <source>J Clin Oncol</source><year>2013</year>; <volume>31</volume>:<fpage>e439</fpage>-<lpage>42</lpage>; PMID:24043743; http://dx.doi.org/<pub-id pub-id-type="doi">10.1200/JCO.2012.47.7521</pub-id><pub-id pub-id-type="pmid">24043743</pub-id></mixed-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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