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

Abstract

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. 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. <i>In silico</i> analysis of publicly available RNA expression data from 308 HGSC samples was used as a confirmatory approach. 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 T_H1 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. Our data indicate that PD-L1 and TIM-3 constitute prognostically relevant biomarkers of active and suppressed immune responses against HGSC, respectively.