Association of Polymerase e-Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1

JAMA Oncol. 2015 Dec;1(9):1319-23. doi: 10.1001/jamaoncol.2015.2151.


Importance: Immune checkpoint inhibitor therapy has shown benefit in various cancers, but their potential in endometrial cancer (EC) is unknown.

Observations: Prediction of neoantigen load was performed using sequencing data from the Cancer Genome Atlas data set. Evaluation of tumor-infiltrating lymphocytes (TILs) and PD-1 and PD-L1 expression was performed in 63 patients with EC referred to our institution. The predicted median (range) neoantigen load (predicted neoepitopes per sample) was proportional to the mutational load: highest in ultramutated polymerase e (POLE) tumors (8342 [628-20 440]), less in hypermutated MSI (541 [146-8063]; P < .001), and lowest in microsatellite-stable tumors (70.5 [7-1877]; P < .001). The POLE and MSI ECs exhibited higher numbers of CD3+ (44.5 vs 21.8; P = .001) and CD8+ (32.8 vs 13.5; P < .001) TILs compared with microsatellite-stable tumors. PD-1 was overexpressed in TILs (81% vs 28%; P < .001) and peritumoral lymphocytes (90% vs 28%; P < .001) of POLE and MSI tumors. PD-L1 expression was infrequently noted in tumor cells but was common in intraepithelial immune cells and more frequent in POLE and MSI tumors (39% vs 13%; P = .02).

Conclusions and relevance: Polymerase e-mutated and MSI ECs are associated with high neoantigen loads and number of TILs, which is counterbalanced by overexpression of PD-1 and PD-L1. Polymerase e-mutated and MSI EC tumors may be excellent candidates for PD-1-targeted immunotherapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, Neoplasm / metabolism
  • B7-H1 Antigen / metabolism
  • CD3 Complex / metabolism
  • CD8 Antigens / metabolism
  • DNA Polymerase II / genetics*
  • Endometrial Neoplasms / genetics*
  • Female
  • Humans
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Microsatellite Instability*
  • Middle Aged
  • Mutation / genetics*
  • Poly-ADP-Ribose Binding Proteins
  • Programmed Cell Death 1 Receptor / metabolism


  • Antigens, Neoplasm
  • B7-H1 Antigen
  • CD274 protein, human
  • CD3 Complex
  • CD8 Antigens
  • PDCD1 protein, human
  • Poly-ADP-Ribose Binding Proteins
  • Programmed Cell Death 1 Receptor
  • DNA Polymerase II
  • POLE protein, human