title: PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer.
abstract: As a negative regulator of T cells, Programmed Death Ligand 1 (PD-L1) is both an indicator and inhibitor of anti-tumor immune responses, which has led to confusion about its prognostic significance. We investigated the primary source of PD-L1 expression in epithelial ovarian cancer and its relationship to tumor-infiltrating lymphocytes (TIL) and associated gene products.
  
  
  
  Tissue microarrays containing high-grade serous carcinomas (HGSC) and endometrioid, clear cell and mucinous ovarian cancers from optimally debulked patients were assessed by immunohistochemistry for expression of PD-L1 and other markers (CD68, CD3, CD8, PD-1, CD103, FoxP3 and CD25). The Cancer Genome Atlas was interrogated for associations between PD-L1 expression and immune-related transcriptional and genomic features of HGSC.
  
  
  
  PD-L1 was primarily expressed by tumor-associated CD68(+) macrophages rather than tumor cells. PD-L1(+) cells frequently co-localized with CD8, CD4 and PD-1(+) TIL, CD25(+)FoxP3(+) Tregs, and other TIL subsets. PD-L1(+) cells were prognostically favorable in HGSC. Moreover, the presence of both PD-L1(+) cells and CD8 TIL was associated with better prognosis than CD8 TIL alone. PD-L1 gene expression was independent of BRCA status. At the transcriptional level, PD-L1 was associated with both cytolytic (granzyme B, T-bet and IFN-γ) and suppressive (PD-1, CTLA-4, LAG3 and IDO-1) gene products.
  
  
  
  PD-L1 is primarily expressed by macrophages in ovarian cancer and is strongly associated with both cytolytic and regulatory TIL subsets, resulting in a net positive association with survival. Tumors containing PD-L1(+) macrophages appear caught in an immunological stalemate that may require multi-pronged immunotherapy to alleviate.
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada. Electronic address: jwebb@bccrc.ca.ca.
authors.forename: John R
authors.initials: JR
authors.lastname: Webb
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada.
authors.forename: Katy
authors.initials: K
authors.lastname: Milne
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Kroeger
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Brad H
authors.initials: BH
authors.lastname: Nelson
mesh_terms: D060890:B7-H1 Antigen / Q000096:biosynthesis* / Q000276:immunology; D000077216:Carcinoma, Ovarian Epithelial; D018284:Cystadenocarcinoma, Serous / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009375:Neoplasms, Glandular and Epithelial / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D046888:Tissue Array Analysis
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human
keywords: Adaptive resistance; Ovarian cancer; PD-L1