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

0505520 - ÚI 2020 US eng J - Článek v odborném periodiku
Fučíková, J. - Raková, J. - Hensler, M. - Kašíková, L. - Belicová, L. - Hladíková, K. - Truxová, I. - Skapa, P. - Laco, J. - Pecen, Ladislav - Práznovec, I. - Halaška, M. - Brtnický, T. - Kodet, R. - Fialová, A. - Pineau, J. - Gey, A. - Tartour, E. - Ryška, A. - Galluzzi, L. - Špíšek, R.
TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer.
Clinical Cancer Research. Roč. 25, č. 15 (2019), s. 4820-4831. ISSN 1078-0432. E-ISSN 1557-3265
Impakt faktor: 10.107, rok: 2019

Purpose: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. 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. 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. 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, 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. Conclusion: Our data indicate that PD-L1 and TIM-3 constitute prognostically relevant biomarkers of active and suppressed immune responses against HGSC, respectively.
Trvalý link: http://hdl.handle.net/11104/0297003