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

May 10, 2019
Source: Clin Cancer Res. 2019 May 10. pii: clincanres.4175.2018. doi: 10.1158/1078-0432.CCR-18-4175. [Epub ahead of print]

Authors: J. Fucikova, J. Rakova, M. Hensler, L. Kasikova, L. Belicová, K. Hladikova, I. Truxova, P. Skapa, J. Laco, L. Pecen, I. Praznovec, M.J.Halaska, T. Brtnicky, R. Kodet, A. Fialová, J. Pineau, A. Gey, E. Tartour, A. Ryska, L. Galluzzi, R. Spisek.


In multiple oncological settings, expression of the co-inhibitory ligand PD-L1 by malignant cells and tumor infiltration by immune cells expressing co-inhibitory 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 amongst 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. Immunohistochemical 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.


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, while 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.