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
- MeSH
- antigen CTLA-4 imunologie metabolismus MeSH
- antigeny nádorové * imunologie metabolismus MeSH
- cílená molekulární terapie metody MeSH
- imunoterapie * metody MeSH
- lidé MeSH
- nádory * imunologie metabolismus terapie MeSH
- únik nádoru z imunitní kontroly imunologie účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
