Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition.
Identifieur interne : 000A24 ( PubMed/Checkpoint ); précédent : 000A23; suivant : 000A25Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition.
Auteurs : Florine A. Eggink [Pays-Bas] ; Inge C. Van Gool [Pays-Bas] ; Alexandra Leary [France] ; Pamela M. Pollock [Australie] ; Emma J. Crosbie [Royaume-Uni] ; Linda Mileshkin [Australie] ; Ekaterina S. Jordanova [Pays-Bas] ; Julien Adam [France] ; Luke Freeman-Mills [Royaume-Uni] ; David N. Church [Royaume-Uni] ; Carien L. Creutzberg [Pays-Bas] ; Marco De Bruyn [Pays-Bas] ; Hans W. Nijman [Pays-Bas] ; Tjalling Bosse [Pays-Bas]Source :
- Oncoimmunology [ 2162-4011 ] ; 2017.
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 POLE exonuclease domain-mutant ECs (POLE-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 POLE-mutant and MSI tumors compared with NSMP and p53-mutants. This was reflected by enhanced immune expression and infiltration in POLE-mutant and MSI tumors in both the TCGA cohort (mRNA expression) and the TransPORTEC cohort (immunohistochemistry) with high infiltration of CD8(+) (90% and 69%), PD-1(+) (73% and 69%) and PD-L1(+) 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(+) 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 POLE-mutant and MSI endometrial tumors suggests sensitivity to immune checkpoint inhibitors.
DOI: 10.1080/2162402X.2016.1264565
PubMed: 28344870
Affiliations:
- Australie, France, Pays-Bas, Royaume-Uni
- Angleterre, Grand Manchester, Groningue (province), Hollande-Méridionale, Hollande-Septentrionale, Oxfordshire
- Amsterdam, Groningue, Groningue (ville), Leyde, Manchester, Oxford
- Université d'Oxford, Université de Groningue, Université de Manchester
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<author><name sortKey="Mileshkin, Linda" sort="Mileshkin, Linda" uniqKey="Mileshkin L" first="Linda" last="Mileshkin">Linda Mileshkin</name>
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<author><name sortKey="Bosse, Tjalling" sort="Bosse, Tjalling" uniqKey="Bosse T" first="Tjalling" last="Bosse">Tjalling Bosse</name>
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<front><div type="abstract" xml:lang="en">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 POLE exonuclease domain-mutant ECs (POLE-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 POLE-mutant and MSI tumors compared with NSMP and p53-mutants. This was reflected by enhanced immune expression and infiltration in POLE-mutant and MSI tumors in both the TCGA cohort (mRNA expression) and the TransPORTEC cohort (immunohistochemistry) with high infiltration of CD8(+) (90% and 69%), PD-1(+) (73% and 69%) and PD-L1(+) 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(+) 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 POLE-mutant and MSI endometrial tumors suggests sensitivity to immune checkpoint inhibitors.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="PubMed-not-MEDLINE" Owner="NLM"><PMID Version="1">28344870</PMID>
<DateCreated><Year>2017</Year>
<Month>03</Month>
<Day>27</Day>
</DateCreated>
<DateRevised><Year>2017</Year>
<Month>08</Month>
<Day>16</Day>
</DateRevised>
<Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Print">2162-4011</ISSN>
<JournalIssue CitedMedium="Print"><Volume>6</Volume>
<Issue>2</Issue>
<PubDate><Year>2017</Year>
</PubDate>
</JournalIssue>
<Title>Oncoimmunology</Title>
<ISOAbbreviation>Oncoimmunology</ISOAbbreviation>
</Journal>
<ArticleTitle>Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition.</ArticleTitle>
<Pagination><MedlinePgn>e1264565</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1080/2162402X.2016.1264565</ELocationID>
<Abstract><AbstractText>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 POLE exonuclease domain-mutant ECs (POLE-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 POLE-mutant and MSI tumors compared with NSMP and p53-mutants. This was reflected by enhanced immune expression and infiltration in POLE-mutant and MSI tumors in both the TCGA cohort (mRNA expression) and the TransPORTEC cohort (immunohistochemistry) with high infiltration of CD8(+) (90% and 69%), PD-1(+) (73% and 69%) and PD-L1(+) 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(+) 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 POLE-mutant and MSI endometrial tumors suggests sensitivity to immune checkpoint inhibitors.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Eggink</LastName>
<ForeName>Florine A</ForeName>
<Initials>FA</Initials>
<AffiliationInfo><Affiliation>Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen , Groningen, the Netherlands.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Van Gool</LastName>
<ForeName>Inge C</ForeName>
<Initials>IC</Initials>
<AffiliationInfo><Affiliation>Department of Pathology, Leiden University Medical Center , Leiden, the Netherlands.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Leary</LastName>
<ForeName>Alexandra</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Department of Medical Oncology, INSERM U981, Gustave Roussy Cancer Center , Villejuif, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Pollock</LastName>
<ForeName>Pamela M</ForeName>
<Initials>PM</Initials>
<AffiliationInfo><Affiliation>Queensland University of Technology (QUT), Translational Research Institute , Brisbane, QLD, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Crosbie</LastName>
<ForeName>Emma J</ForeName>
<Initials>EJ</Initials>
<AffiliationInfo><Affiliation>Institute of Cancer Sciences, University of Manchester, St Marys Hospital , Manchester, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Mileshkin</LastName>
<ForeName>Linda</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>Division of Cancer Medicine, Peter MacCallum Cancer Centre , East Melbourne, VIC, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Jordanova</LastName>
<ForeName>Ekaterina S</ForeName>
<Initials>ES</Initials>
<AffiliationInfo><Affiliation>Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands; Center for Gynecological Oncology Amsterdam, VU Medical Center, Amsterdam, the Netherlands.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Adam</LastName>
<ForeName>Julien</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Medical Oncology, INSERM U981, Gustave Roussy Cancer Center , Villejuif, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Freeman-Mills</LastName>
<ForeName>Luke</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>Tumour Genomics and Immunology Group, Oxford Centre for Cancer Gene Research, The Wellcome Trust Centre for Human Genetics, University of Oxford , Oxford, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Church</LastName>
<ForeName>David N</ForeName>
<Initials>DN</Initials>
<AffiliationInfo><Affiliation>Tumour Genomics and Immunology Group, Oxford Centre for Cancer Gene Research, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Oxford Cancer Centre, Churchill Hospital, Oxford, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Creutzberg</LastName>
<ForeName>Carien L</ForeName>
<Initials>CL</Initials>
<AffiliationInfo><Affiliation>Department of Clinical Oncology, Leiden University Medical Center , Leiden, the Netherlands.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>De Bruyn</LastName>
<ForeName>Marco</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen , Groningen, the Netherlands.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Nijman</LastName>
<ForeName>Hans W</ForeName>
<Initials>HW</Initials>
<AffiliationInfo><Affiliation>Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen , Groningen, the Netherlands.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Bosse</LastName>
<ForeName>Tjalling</ForeName>
<Initials>T</Initials>
<AffiliationInfo><Affiliation>Department of Pathology, Leiden University Medical Center , Leiden, the Netherlands.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2016</Year>
<Month>12</Month>
<Day>09</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>Oncoimmunology</MedlineTA>
<NlmUniqueID>101570526</NlmUniqueID>
<ISSNLinking>2162-4011</ISSNLinking>
</MedlineJournalInfo>
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<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Checkpoint inhibition</Keyword>
<Keyword MajorTopicYN="N">endometrial cancer</Keyword>
<Keyword MajorTopicYN="N">high-risk</Keyword>
<Keyword MajorTopicYN="N">molecular classification</Keyword>
<Keyword MajorTopicYN="N">tumor-infiltrating lymphocytes</Keyword>
</KeywordList>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year>
<Month>10</Month>
<Day>12</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="revised"><Year>2016</Year>
<Month>11</Month>
<Day>16</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="accepted"><Year>2016</Year>
<Month>11</Month>
<Day>17</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez"><Year>2017</Year>
<Month>3</Month>
<Day>28</Day>
<Hour>6</Hour>
<Minute>0</Minute>
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<PubMedPubDate PubStatus="pubmed"><Year>2017</Year>
<Month>3</Month>
<Day>28</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="medline"><Year>2017</Year>
<Month>3</Month>
<Day>28</Day>
<Hour>6</Hour>
<Minute>1</Minute>
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</History>
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<ArticleId IdType="doi">10.1080/2162402X.2016.1264565</ArticleId>
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<affiliations><list><country><li>Australie</li>
<li>France</li>
<li>Pays-Bas</li>
<li>Royaume-Uni</li>
</country>
<region><li>Angleterre</li>
<li>Grand Manchester</li>
<li>Groningue (province)</li>
<li>Hollande-Méridionale</li>
<li>Hollande-Septentrionale</li>
<li>Oxfordshire</li>
</region>
<settlement><li>Amsterdam</li>
<li>Groningue</li>
<li>Groningue (ville)</li>
<li>Leyde</li>
<li>Manchester</li>
<li>Oxford</li>
</settlement>
<orgName><li>Université d'Oxford</li>
<li>Université de Groningue</li>
<li>Université de Manchester</li>
</orgName>
</list>
<tree><country name="Pays-Bas"><region name="Groningue (province)"><name sortKey="Eggink, Florine A" sort="Eggink, Florine A" uniqKey="Eggink F" first="Florine A" last="Eggink">Florine A. Eggink</name>
</region>
<name sortKey="Bosse, Tjalling" sort="Bosse, Tjalling" uniqKey="Bosse T" first="Tjalling" last="Bosse">Tjalling Bosse</name>
<name sortKey="Creutzberg, Carien L" sort="Creutzberg, Carien L" uniqKey="Creutzberg C" first="Carien L" last="Creutzberg">Carien L. Creutzberg</name>
<name sortKey="De Bruyn, Marco" sort="De Bruyn, Marco" uniqKey="De Bruyn M" first="Marco" last="De Bruyn">Marco De Bruyn</name>
<name sortKey="Jordanova, Ekaterina S" sort="Jordanova, Ekaterina S" uniqKey="Jordanova E" first="Ekaterina S" last="Jordanova">Ekaterina S. Jordanova</name>
<name sortKey="Nijman, Hans W" sort="Nijman, Hans W" uniqKey="Nijman H" first="Hans W" last="Nijman">Hans W. Nijman</name>
<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>
</country>
<country name="France"><noRegion><name sortKey="Leary, Alexandra" sort="Leary, Alexandra" uniqKey="Leary A" first="Alexandra" last="Leary">Alexandra Leary</name>
</noRegion>
<name sortKey="Adam, Julien" sort="Adam, Julien" uniqKey="Adam J" first="Julien" last="Adam">Julien Adam</name>
</country>
<country name="Australie"><noRegion><name sortKey="Pollock, Pamela M" sort="Pollock, Pamela M" uniqKey="Pollock P" first="Pamela M" last="Pollock">Pamela M. Pollock</name>
</noRegion>
<name sortKey="Mileshkin, Linda" sort="Mileshkin, Linda" uniqKey="Mileshkin L" first="Linda" last="Mileshkin">Linda Mileshkin</name>
</country>
<country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Crosbie, Emma J" sort="Crosbie, Emma J" uniqKey="Crosbie E" first="Emma J" last="Crosbie">Emma J. Crosbie</name>
</region>
<name sortKey="Church, David N" sort="Church, David N" uniqKey="Church D" first="David N" last="Church">David N. Church</name>
<name sortKey="Freeman Mills, Luke" sort="Freeman Mills, Luke" uniqKey="Freeman Mills L" first="Luke" last="Freeman-Mills">Luke Freeman-Mills</name>
</country>
</tree>
</affiliations>
</record>
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