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

Jitka Fučíková ,Michal Hensler,Roman Kodet,Michael J Halaska,Lucie Belicova,Lorenzo Galluzzi,Alain Gey,Ladislav Pecen,Ján Laco ,Tomáš Brtnický ,Ivan Práznovec ,Alena Fialová ,Aleš Ryška ,Éric Tartour ,Iva Truxová ,Judith Pineau ,Petr Škapa ,Lenka Kašíková ,Kamila Hladíková ,Jana Raková ,Radek Špíšek

doi:10.1158/1078-0432.c.6528111

Abstract

<div>AbstractPurpose: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.</div>

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