A48: POLE proofreading mutations elicit an anti-tumour immune response in endometrial cancer
1Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands,2University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, Groningen, The Netherlands,3Molecular and Population Genetics Laboratory, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK,4Immunity Theme, NIHR Oxford Comprehensive Biomedical Research Centre, The Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK,5Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands,6Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands,7Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK,8Oxford Cancer Centre, Churchill Hospital, Oxford, UK
Recent studies have shown that 7-12% of endometrial cancers (ECs) are ultramutated due to mutation in the proofreading exonuclease domain of the DNA replicase POLE. Notably, these tumours have an excellent prognosis. In view of the emerging association between mutation burden, immune response and clinical outcome in cancer, we investigated whether POLE-mutant ECs showed evidence of increased immunogenicity.
We examined immune infiltration and activation according to POLE proofreading mutation in a molecularly defined EC cohort including 47 POLE proofreading mutant tumours, together with microsatellite stable (MSS) and unstable (MSI) ECs lacking POLE mutation (n=54 and n=49, respectively). We sought to confirm our results by analysis of RNAseq data from the TCGA EC series and used the same series to examine whether differences in immune infiltration could be explained by an enrichment of immunogenic neo-epitopes in POLE-mutant ECs.
POLE-mutant ECs displayed a striking cytotoxic T cell response illustrated by greater numbers of intratumoural CD8+ cells than MSS and MSI tumours (median 5.9 /HPF vs. 0.9 vs. 2.6, P<0.0001and P<0.001 respectively), increased CD8A expression (3.0 fold vs. MSS, P=0.002), enrichment for a tumor-infiltrating T cell gene signature (P<0.001), and strong upregulation of the T cell cytotoxic differentiation and effector markers T-bet (1.9 fold, P=0.006), Eomes, IFNG, PRF and granzyme B (1.9 to 3.6 fold vs. MSS, P=0.0003 to 0.02) This was accompanied by upregulation of immune checkpoint/T cell exhaustion markers, consistent with chronic antigen exposure. In-silico analysis confirmed that POLE-mutant cancers are predicted to display more antigenic neo-epitopes than other ECs, providing a potential explanation for our findings.
Ultramutated POLE proofreading-mutant ECs are characterized by a robust intratumoral T cell response, which correlates with, and may be caused by an enrichment of antigenic neo-peptides. Our study provides a plausible mechanism for the excellent prognosis of these cancers, and suggests that patients with POLE proofreading mutant tumours of other histologies may be promising candidates for immune checkpoint inhibitor therapy.