POLE Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer.

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.

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.

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.

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.

• Authors: Inge C van Gool, Florine A Eggink, Luke Freeman-Mills, Ellen Stelloo, Emanuele Marchi, Marco de Bruyn, Claire Palles, Remi A Nout, Cor D de Kroon, Elisabeth M Osse, Paul Klenerman, Carien L Creutzberg, Ian Pm Tomlinson, Vincent Thbm Smit, Hans W Nijman, Tjalling Bosse, David N Church
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 14 Pg. 3347-3355 (Jul 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25878334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Poly-ADP-Ribose Binding Proteins
• DNA Polymerase II
• POLE protein, human

Topics

• Cohort Studies
• DNA Mutational Analysis
• DNA Polymerase II (genetics, immunology)
• Endometrial Neoplasms (genetics, immunology)
• Female
• Fluorescent Antibody Technique
• Humans
• Immunohistochemistry
• Lymphocytes, Tumor-Infiltrating (immunology)
• Mutation
• Poly-ADP-Ribose Binding Proteins
• Polymerase Chain Reaction