Data from <i>POLE</i> Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> 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 <i>POLE</i>. 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 <i>POLE</i>-mutant endometrial cancers showed evidence of increased immunogenicity.</p><p><b>Experimental Design:</b> We examined immune infiltration and activation according to tumor <i>POLE</i> proofreading mutation in a molecularly defined endometrial cancer cohort including 47 <i>POLE</i>-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 <i>POLE</i>-mutant endometrial cancers.</p><p><b>Results:</b> Compared with other endometrial cancers, <i>POLE</i> mutants displayed an enhanced cytotoxic T-cell response, evidenced by increased numbers of CD8<sup>+</sup> 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. <i>In silico</i> analysis confirmed that <i>POLE</i>-mutant cancers are predicted to display more antigenic neoepitopes than other endometrial cancers, providing a potential explanation for our findings.</p><p><b>Conclusions:</b> Ultramutated <i>POLE</i> 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. <i>Clin Cancer Res; 21(14); 3347–55. ©2015 AACR</i>.</p></div>