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-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. 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 T1 polarization and cytotoxic orientation that enabled superior clinical benefits. Moreover, PD-1TIM-3CD8 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.