title: 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.
abstract: OBJECTIVE
  Immune checkpoint inhibitor therapy has shown benefit in various cancers, but their potential in endometrial cancer (EC) is unknown.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Howitt
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts3Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sachet A
authors.initials: SA
authors.lastname: Shukla
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lauren L
authors.initials: LL
authors.lastname: Ritterhouse
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jaclyn C
authors.initials: JC
authors.lastname: Watkins
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Scott
authors.initials: S
authors.lastname: Rodig
authors.affiliation: Medical Gynecologic Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Stover
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Strickland
authors.affiliation: Division of Genomic Stability and DNA Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts3Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
authors.affiliation: Medical Gynecologic Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Matulonis
authors.affiliation: Medical Gynecologic Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Panagiotis A
authors.initials: PA
authors.lastname: Konstantinopoulos
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism; D060890:B7-H1 Antigen / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D004257:DNA Polymerase II / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism*; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000075223:Poly-ADP-Ribose Binding Proteins; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D017252:CD3 Complex; D016827:CD8 Antigens; C105992:PDCD1 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D061026:Programmed Cell Death 1 Receptor; D004257:DNA Polymerase II; C119525:POLE protein, human