Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer

TLDR

PD‑1–blocking antibodies have produced durable responses in many cancers, yet their benefit is inconsistent and can cause adverse effects, and the determinants of sensitivity versus resistance remain poorly understood. This study sought to identify and characterize a POLE‑mutant endometrial cancer patient who exhibited an exceptional response to pembrolizumab. Targeted genomic profiling of the patient’s pretreatment tumor revealed a DNA polymerase epsilon (POLE) mutation associated with an ultramutator phenotype. The patient’s POLE‑mutant tumor displayed high mutational burden and elevated immune‑checkpoint gene expression, and TCGA data confirm that POLE mutations predict strong responses to immune checkpoint inhibitors, supporting their use in this subset of endometrial cancers.

Abstract

Antibodies that target the immune checkpoint receptor programmed cell death protein 1 (PD-1) have resulted in prolonged and beneficial responses toward a variety of human cancers. However, anti-PD-1 therapy in some patients provides no benefit and/or results in adverse side effects. The factors that determine whether patients will be drug sensitive or resistant are not fully understood; therefore, genomic assessment of exceptional responders can provide important insight into patient response. Here, we identified a patient with endometrial cancer who had an exceptional response to the anti-PD-1 antibody pembrolizumab. Clinical grade targeted genomic profiling of a pretreatment tumor sample from this individual identified a mutation in DNA polymerase epsilon (POLE) that associated with an ultramutator phenotype. Analysis of The Cancer Genome Atlas (TCGA) revealed that the presence of POLE mutation associates with high mutational burden and elevated expression of several immune checkpoint genes. Together, these data suggest that cancers harboring POLE mutations are good candidates for immune checkpoint inhibitor therapy.