title: Characterization of immune regulatory molecules B7-H4 and PD-L1 in low and high grade endometrial tumors.
abstract: The objective of this investigation was to characterize the expression landscape of immune regulatory molecules programmed death-ligand-1 (PD-L1, B7-H1) and B7-H4 in a cohort of endometrial tumors across the spectrum of grade and histology.
  
  
  
  With institutional review board approval, 70 endometrial tumors from patients with known clinical outcomes were identified representing a spectrum of grade and histology. Immunohistochemistry (IHC) was performed for PD-L1 and B7-H4 and scored. Microsatellite instability (MSI) status was assessed for endometrioid tumors using the institutional IHC assay for expression of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2. RNA sequencing data from the Cancer Genome Atlas was queried for expression levels of CD274 (PD-L1 protein) and VTCN1 (B7-H4) across molecular subtypes of endometrial carcinoma and were correlated with a T cell infiltration index.
  
  
  
  We identified 40 low grade endometrioid tumors and a cohort of 30 high grade tumors. PD-L1 expression was observed in both high and low grade endometrial tumors (56% vs 35%, p=0.07). In the low grade tumors, PD-L1 expression was associated with MSI status (p<0.01). The high grade cohort had similar rates of PD-L1 expression compared to low grade MSI tumor (56% and 62% respectively), and both were distinct from low grade MSS tumors (22%, p<0.05). High (3+) B7-H4 positive cells were observed in both high and low grade carcinomas (33% and 31% respectively). RNA profiling data from confirmed highest CD274 expression in POLE and MSI tumors that was linearly correlated with T cell infiltration, while VTCN1 expression appeared consistent across molecular subtypes.
  
  
  
  While PD-L1 expression correlated with MSI and high grade tumors, B7-H4 expression was independent of grade, histology and immune cell infiltration. The development and testing of multi-agent therapeutics targeting PD-L1 and B7-H4 may be a novel strategy for endometrial tumors.
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States; Gynecologic Oncology Division, Vincent Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Bregar
authors.affiliation: Jounce Therapeutics, Inc., Cambridge, MA, United States.
authors.forename: Amit
authors.initials: A
authors.lastname: Deshpande
authors.affiliation: Jounce Therapeutics, Inc., Cambridge, MA, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Grange
authors.affiliation: Jounce Therapeutics, Inc., Cambridge, MA, United States.
authors.forename: Tong
authors.initials: T
authors.lastname: Zi
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stall
authors.affiliation: Jounce Therapeutics, Inc., Cambridge, MA, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: Hirsch
authors.affiliation: Jounce Therapeutics, Inc., Cambridge, MA, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Reeves
authors.affiliation: Jounce Therapeutics, Inc., Cambridge, MA, United States.
authors.forename: Sriram
authors.initials: S
authors.lastname: Sathyanarayanan
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States; Gynecologic Oncology Division, Vincent Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States.
authors.forename: Whitfield B
authors.initials: WB
authors.lastname: Growdon
authors.affiliation: Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States; Gynecologic Oncology Division, Vincent Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston, MA 02114, United States. Electronic address: brueda@mgh.harvard.edu.
authors.forename: Bo R
authors.initials: BR
authors.lastname: Rueda
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000276:immunology*; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016889:Endometrial Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053842:Microsatellite Instability; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D016612:Paraffin Embedding; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human
keywords: B7-H4 expression; Endometrial carcinoma; Immune checkpoint inhibition; PD-L1 over-expression