PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer

• Published in: Gynecologic oncology Vol. 141; no. 2; pp. 293 - 302
• Main Authors: Webb, John R., Milne, Katy, Kroeger, David R., Nelson, Brad H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2016
• Subjects: Adaptive resistance; B7-H1 Antigen - biosynthesis; B7-H1 Antigen - immunology; Carcinoma, Ovarian Epithelial; Cystadenocarcinoma, Serous - immunology; Cystadenocarcinoma, Serous - metabolism; Cystadenocarcinoma, Serous - pathology; Female; Hematology, Oncology and Palliative Medicine; Humans; Immunohistochemistry; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - pathology; Macrophages - immunology; Macrophages - metabolism; Macrophages - pathology; Neoplasms, Glandular and Epithelial - immunology; Neoplasms, Glandular and Epithelial - metabolism; Neoplasms, Glandular and Epithelial - pathology; Obstetrics and Gynecology; Ovarian cancer; Ovarian Neoplasms - immunology; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; PD-L1; Prognosis; Tissue Array Analysis; PD-L1; Adaptive resistance; Ovarian cancer
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2016.03.008

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. •Expression of PD-L1 in ovarian cancer was revaluated using modern antibody reagents•PD-L1 expression positively correlated with tumor infiltrating lymphocytes•PD-L1 expression was a favorable prognostic feature of high grade serous cancer