Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition
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Auteurs : Florine A. Eggink ; Inge C. Van Gool ; Alexandra Leary [France] ; Pamela M. Pollock [Australie] ; Emma J. Crosbie [Royaume-Uni] ; Linda Mileshkin [Australie] ; Ekaterina S. Jordanova ; Julien Adam [France] ; Luke Freeman-Mills [Royaume-Uni] ; David N. Church [Royaume-Uni] ; Carien L. Creutzberg ; Marco De Bruyn ; Hans W. Nijman ; Tjalling BosseSource :
- Oncoimmunology [ 2162-4011 ] ; 2016.
Abstract
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
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DOI: 10.1080/2162402X.2016.1264565
PubMed: 28344870
PubMed Central: 5353925
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Florine A. Eggink<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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></affiliation><affiliation><nlm:aff id="af0002"><institution>Department of Pathology, Leiden University Medical Center</institution>, Leiden,<country>the Netherlands</country></nlm:aff><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></affiliation><affiliation><nlm:aff id="af0002"><institution>Department of Pathology, Leiden University Medical Center</institution>, Leiden,<country>the Netherlands</country></nlm:aff><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></affiliation><affiliation><nlm:aff id="af0007"><institution>Center for Gynecological Oncology Amsterdam, VU Medical Center</institution>, Amsterdam,<country>the Netherlands</country></nlm:aff><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></affiliation><affiliation><nlm:aff id="af0007"><institution>Center for Gynecological Oncology Amsterdam, VU Medical Center</institution>, Amsterdam,<country>the Netherlands</country></nlm:aff><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></affiliation><affiliation><nlm:aff id="af0010"><institution>Department of Clinical Oncology, Leiden University Medical Center</institution>, Leiden,<country>the Netherlands</country></nlm:aff><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></affiliation><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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></affiliation><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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></affiliation><affiliation><nlm:aff id="af0002"><institution>Department of Pathology, Leiden University Medical Center</institution>, Leiden,<country>the Netherlands</country></nlm:aff><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></affiliation>Le document en format XML
<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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></affiliation></author><author><name sortKey="Leary, Alexandra" sort="Leary, Alexandra" uniqKey="Leary A" first="Alexandra" last="Leary">Alexandra Leary</name><affiliation wicri:level="1"><nlm:aff id="af0003"><institution>Department of Medical Oncology, INSERM U981, Gustave Roussy Cancer Center</institution>, Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pollock, Pamela M" sort="Pollock, Pamela M" uniqKey="Pollock P" first="Pamela M." last="Pollock">Pamela M. 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Jordanova</name><affiliation><nlm:aff id="af0002"><institution>Department of Pathology, Leiden University Medical Center</institution>, Leiden,<country>the Netherlands</country></nlm:aff><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></affiliation><affiliation><nlm:aff id="af0007"><institution>Center for Gynecological Oncology Amsterdam, VU Medical Center</institution>, Amsterdam,<country>the Netherlands</country></nlm:aff><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></affiliation></author><author><name sortKey="Adam, Julien" sort="Adam, Julien" uniqKey="Adam J" first="Julien" last="Adam">Julien Adam</name><affiliation wicri:level="1"><nlm:aff id="af0003"><institution>Department of Medical Oncology, INSERM U981, Gustave Roussy Cancer Center</institution>, Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></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 wicri:level="1"><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><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></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 wicri:level="1"><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><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af0009"><institution>Oxford Cancer Centre, Churchill Hospital</institution>, Oxford,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></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><idno type="wicri:Area/Pmc/Curation">002673</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">002673</idno><idno type="wicri:Area/Pmc/Checkpoint">000854</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000854</idno><idno type="wicri:source">PubMed</idno><idno type="wicri:Area/PubMed/Corpus">001470</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001470</idno><idno type="wicri:Area/PubMed/Curation">001448</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001448</idno><idno type="wicri:Area/PubMed/Checkpoint">001448</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001448</idno><idno type="wicri:Area/Ncbi/Merge">004533</idno><idno type="wicri:Area/Ncbi/Curation">004533</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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></affiliation></author><author><name sortKey="Leary, Alexandra" sort="Leary, Alexandra" uniqKey="Leary A" first="Alexandra" last="Leary">Alexandra Leary</name><affiliation wicri:level="1"><nlm:aff id="af0003"><institution>Department of Medical Oncology, INSERM U981, Gustave Roussy Cancer Center</institution>, Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></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 wicri:level="1"><nlm:aff id="af0004"><institution>Queensland University of Technology (QUT), Translational Research Institute</institution>, Brisbane, QLD,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></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 wicri:level="1"><nlm:aff id="af0005"><institution>Institute of Cancer Sciences, University of Manchester, St Marys Hospital</institution>, Manchester,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mileshkin, Linda" sort="Mileshkin, Linda" uniqKey="Mileshkin L" first="Linda" last="Mileshkin">Linda Mileshkin</name><affiliation wicri:level="1"><nlm:aff id="af0006"><institution>Division of Cancer Medicine, Peter MacCallum Cancer Centre</institution>, East Melbourne, VIC,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></affiliation><affiliation><nlm:aff id="af0007"><institution>Center for Gynecological Oncology Amsterdam, VU Medical Center</institution>, Amsterdam,<country>the Netherlands</country></nlm:aff><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></affiliation></author><author><name sortKey="Adam, Julien" sort="Adam, Julien" uniqKey="Adam J" first="Julien" last="Adam">Julien Adam</name><affiliation wicri:level="1"><nlm:aff id="af0003"><institution>Department of Medical Oncology, INSERM U981, Gustave Roussy Cancer Center</institution>, Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></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 wicri:level="1"><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><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></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 wicri:level="1"><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><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af0009"><institution>Oxford Cancer Centre, Churchill Hospital</institution>, Oxford,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></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><wicri:noCountry code="nlm country">the Netherlands</wicri:noCountry></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 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