Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer
Janice M. Mehnert, … , Jonathan Cheng, Shridar Ganesan
Janice M. Mehnert, … , Jonathan Cheng, Shridar Ganesan
Published May 9, 2016
Citation Information: J Clin Invest. 2016;126(6):2334-2340. https://doi.org/10.1172/JCI84940.
View: Text | PDF
Brief Report Oncology

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

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.

Authors

Janice M. Mehnert, Anshuman Panda, Hua Zhong, Kim Hirshfield, Sherri Damare, Katherine Lane, Levi Sokol, Mark N. Stein, Lorna Rodriguez-Rodriquez, Howard L. Kaufman, Siraj Ali, Jeffrey S. Ross, Dean C. Pavlick, Gyan Bhanot, Eileen P. White, Robert S. DiPaola, Ann Lovell, Jonathan Cheng, Shridar Ganesan

×

Figure 3

Expression of immune signatures in MSS, MSI, and POLE endometrial cancers in the TCGA endometrial cancer data set.

Options: View larger image (or click on image) Download as PowerPoint
Expression of immune signatures in MSS, MSI, and POLE endometrial cancer...
(A) Expression of a set of immune checkpoint and lymphocyte-associated genes as assayed by RNA sequencing in POLE-mutant, MSI, and MSS endometrial cancers. (B) Estimated proportion representation of some leukocyte subsets, as calculated by CIBERSORT, for POLE-mutant, MSI, and MSS endometrial cancers. (C) Distribution of lymphocyte infiltration scores in histological images of a set of POLE-mutant, MSI, and MSS endometrial cancers. Representative images associated with scores of 1 and 3 are shown to the right. Original magnification, ×20. A 2-sided Wilcoxon rank-sum test was used in all cases to determine P values. P <0.05 was considered statistically significant. Number of samples: 27 POLE, 64 MSI, 104 MSS (A); 12 POLE, 20 MSI, 28 MSS (B); 12 POLE, 10 MSI, 10 MSS (C). For the remaining samples not shown in B, CIBERSORT provided a P value ≥ 0.05. Box plots (shown in B and C) use the following default convention: the horizontal line represents the median value, the box covers the interquartile range (IQR), the whiskers cover values within 1.5 IQR beyond the box, and values beyond 1.5 IQR are represented as dots. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.