TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer

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-naive 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.