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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.

Publication ,  Journal Article
Howitt, BE; Shukla, SA; Sholl, LM; Ritterhouse, LL; Watkins, JC; Rodig, S; Stover, E; Strickland, KC; D'Andrea, AD; Wu, CJ; Matulonis, UA ...
Published in: JAMA Oncol
December 2015

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.

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Published In

JAMA Oncol

DOI

EISSN

2374-2445

Publication Date

December 2015

Volume

1

Issue

9

Start / End Page

1319 / 1323

Location

United States

Related Subject Headings

  • Programmed Cell Death 1 Receptor
  • Poly-ADP-Ribose Binding Proteins
  • Mutation
  • Middle Aged
  • Microsatellite Instability
  • Lymphocytes, Tumor-Infiltrating
  • Humans
  • Female
  • Endometrial Neoplasms
  • DNA Polymerase II
 

Citation

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Chicago
ICMJE
MLA
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Howitt, B. E., Shukla, S. A., Sholl, L. M., Ritterhouse, L. L., Watkins, J. C., Rodig, S., … Konstantinopoulos, P. A. (2015). 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, 1(9), 1319–1323. https://doi.org/10.1001/jamaoncol.2015.2151
Howitt, Brooke E., Sachet A. Shukla, Lynette M. Sholl, Lauren L. Ritterhouse, Jaclyn C. Watkins, Scott Rodig, Elizabeth Stover, et al. “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 1, no. 9 (December 2015): 1319–23. https://doi.org/10.1001/jamaoncol.2015.2151.
Howitt, Brooke E., et al. “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, vol. 1, no. 9, Dec. 2015, pp. 1319–23. Pubmed, doi:10.1001/jamaoncol.2015.2151.
Howitt BE, Shukla SA, Sholl LM, Ritterhouse LL, Watkins JC, Rodig S, Stover E, Strickland KC, D’Andrea AD, Wu CJ, Matulonis UA, Konstantinopoulos PA. 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):1319–1323.

Published In

JAMA Oncol

DOI

EISSN

2374-2445

Publication Date

December 2015

Volume

1

Issue

9

Start / End Page

1319 / 1323

Location

United States

Related Subject Headings

  • Programmed Cell Death 1 Receptor
  • Poly-ADP-Ribose Binding Proteins
  • Mutation
  • Middle Aged
  • Microsatellite Instability
  • Lymphocytes, Tumor-Infiltrating
  • Humans
  • Female
  • Endometrial Neoplasms
  • DNA Polymerase II