PURPOSE: In multiple oncological settings, expression of the coinhibitory ligand PD-L1 by malignant cells and tumor infiltration by immune cells expressing coinhibitory receptors such as PD-1, CTLA4, LAG-3, or TIM-3 conveys prognostic or predictive information. Conversely, the impact of these features of the tumor microenvironment on disease outcome among high-grade serous carcinoma (HGSC) patients remains controversial. EXPERIMENTAL DESIGN: We harnessed a retrospective cohort of 80 chemotherapy-naïve HGSC patients to investigate PD-L1 expression and tumor infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ dendritic cells as well as by PD-1+, CTLA4+, LAG-3+, and TIM-3+ cells in relation with prognosis and function orientation of the tumor microenvironment. IHC data were complemented with transcriptomic and functional studies on a second prospective cohort of freshly resected HGSC samples. In silico analysis of publicly available RNA expression data from 308 HGSC samples was used as a confirmatory approach. RESULTS: High levels of PD-L1 and high densities of PD-1+ cells in the microenvironment of HGSCs were strongly associated with an immune contexture characterized by a robust TH1 polarization and cytotoxic orientation that enabled superior clinical benefits. Moreover, PD-1+TIM-3+CD8+ T cells presented all features of functional exhaustion and correlated with poor disease outcome. However, although PD-L1 levels and tumor infiltration by TIM-3+ cells improved patient stratification based on the intratumoral abundance of CD8+ T cells, the amount of PD-1+ cells failed to do so. CONCLUSIONS: Our data indicate that PD-L1 and TIM-3 constitute prognostically relevant biomarkers of active and suppressed immune responses against HGSC, respectively.

• MeSH
• antigen CTLA-4 imunologie   metabolismus   MeSH
• antigeny CD274 imunologie   metabolismus   MeSH
• buněčný receptor 2 viru hepatitidy A imunologie   metabolismus   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• dospělí MeSH
• epiteliální ovariální karcinom imunologie   metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny asociované s lyzozomy imunologie   metabolismus   MeSH
• míra přežití MeSH
• nádorové biomarkery imunologie   metabolismus   MeSH
• nádorové proteiny imunologie   metabolismus   MeSH
• prognóza MeSH
• regulace genové exprese u nádorů * MeSH
• retrospektivní studie MeSH
• senioři MeSH
• serózní cystadenokarcinom imunologie   metabolismus   patologie   MeSH
• tumor infiltrující lymfocyty imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• antigen CTLA-4 MeSH
• antigeny CD274 MeSH
• buněčný receptor 2 viru hepatitidy A MeSH
• CD274 protein, human MeSH Prohlížeč
• CTLA4 protein, human MeSH Prohlížeč
• HAVCR2 protein, human MeSH Prohlížeč
• LAMP3 protein, human MeSH Prohlížeč
• membránové glykoproteiny asociované s lyzozomy MeSH
• nádorové biomarkery MeSH
• nádorové proteiny MeSH