POLE proofreading mutation, immune response and prognosis in endometrial cancer

Inge C Van Gool,Tjalling Bosse,David N Church

doi:10.1080/2162402x.2015.1072675

Abstract

ABSTRACTEndometrial cancers (ECs) with POLE proofreading mutations are typified by ultramutation and excellent prognosis. We investigated whether these were related, and found that POLE-mutant ECs display a robust T cell response that corresponds to an enrichment of antigenic tumor neopeptides. Enhanced immunogenicity may explain the favorable outcome of POLE-mutant ECs.

Highlights

The proofreading exonuclease activity intrinsic to the replicative DNA polymerases epsilon and delta (Pols e and d) is essential to maintain fidelity of DNA replication and prevent mutagenesis
Perhaps less predictably, they have an excellent prognosis.[3,4]. We hypothesized that these two characteristics may be related—that tumor neopeptides caused by ultramutation may stimulate a cytolytic immune response, analogous to previous observations in hypermutated mismatch repair-deficient colorectal cancers (CRCs).[5]
Following the observation that POLE proofreading-mutants had a higher density of tumor-infiltrating lymphocytes (TILs) than other Endometrial cancers (ECs), we confirmed that this represented a CD8+ cytotoxic T cell infiltrate likely to be capable of cytolytic activity, as evidenced by co-staining for the activation marker

Summary

Introduction

The proofreading exonuclease activity intrinsic to the replicative DNA polymerases epsilon and delta (Pols e and d) is essential to maintain fidelity of DNA replication and prevent mutagenesis. In keeping with the essential contribution of polymerase proofreading to replication fidelity, POLE proofreading-mutant ECs are ultramutated.[3] perhaps less predictably, they have an excellent prognosis.[3,4] We hypothesized that these two characteristics may be related—that tumor neopeptides caused by ultramutation may stimulate a cytolytic immune response, analogous to previous observations in hypermutated mismatch repair-deficient CRCs.[5] In a recent study,[6] we investigated this in two large EC cohorts.

Results

Conclusion