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POLE Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2015 Jul 15; Vol. 21 (14), pp. 3347-3355. Date of Electronic Publication: 2015 Apr 15. - Publication Year :
- 2015
-
Abstract
- Purpose: Recent studies have shown that 7% to 12% of endometrial cancers are ultramutated due to somatic mutation in the proofreading exonuclease domain of the DNA replicase POLE. Interestingly, these tumors have an excellent prognosis. In view of the emerging data linking mutation burden, immune response, and clinical outcome in cancer, we investigated whether POLE-mutant endometrial cancers showed evidence of increased immunogenicity.<br />Experimental Design: We examined immune infiltration and activation according to tumor POLE proofreading mutation in a molecularly defined endometrial cancer cohort including 47 POLE-mutant tumors. We sought to confirm our results by analysis of RNAseq data from the TCGA endometrial cancer series and used the same series to examine whether differences in immune infiltration could be explained by an enrichment of immunogenic neoepitopes in POLE-mutant endometrial cancers.<br />Results: Compared with other endometrial cancers, POLE mutants displayed an enhanced cytotoxic T-cell response, evidenced by increased numbers of CD8(+) tumor-infiltrating lymphocytes and CD8A expression, enrichment for a tumor-infiltrating T-cell gene signature, and strong upregulation of the T-cell cytotoxic differentiation and effector markers T-bet, Eomes, IFNG, PRF, and granzyme B. This was accompanied by upregulation of T-cell exhaustion markers, consistent with chronic antigen exposure. In silico analysis confirmed that POLE-mutant cancers are predicted to display more antigenic neoepitopes than other endometrial cancers, providing a potential explanation for our findings.<br />Conclusions: Ultramutated POLE proofreading-mutant endometrial cancers are characterized by a robust intratumoral T-cell response, which correlates with, and may be caused by an enrichment of antigenic neopeptides. Our study provides a plausible mechanism for the excellent prognosis of these cancers.<br /> (©2015 American Association for Cancer Research.)
- Subjects :
- Cohort Studies
DNA Mutational Analysis
DNA Polymerase II immunology
Female
Fluorescent Antibody Technique
Humans
Immunohistochemistry
Lymphocytes, Tumor-Infiltrating immunology
Poly-ADP-Ribose Binding Proteins
Polymerase Chain Reaction
DNA Polymerase II genetics
Endometrial Neoplasms genetics
Endometrial Neoplasms immunology
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 21
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 25878334
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-15-0057