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TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer
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SYSNO ASEP 0505520 Document Type J - Journal Article R&D Document Type The record was not marked in the RIV Subsidiary J Ostatní články Title TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer Author(s) Fučíková, J. (CZ)
Raková, J. (CZ)
Hensler, M. (CZ)
Kašíková, L. (CZ)
Belicová, L. (CZ)
Hladíková, K. (CZ)
Truxová, I. (CZ)
Skapa, P. (CZ)
Laco, J. (CZ)
Pecen, Ladislav (UIVT-O) RID, SAI, ORCID
Práznovec, I. (CZ)
Halaška, M. (CZ)
Brtnický, T. (CZ)
Kodet, R. (CZ)
Fialová, A. (CZ)
Pineau, J. (FR)
Gey, A. (FR)
Tartour, E. (FR)
Ryška, A. (CZ)
Galluzzi, L. (US)
Špíšek, R. (CZ)Source Title Clinical Cancer Research. - : American Association for Cancer Research - ISSN 1078-0432
Roč. 25, č. 15 (2019), s. 4820-4831Language eng - English Country US - United States DOI 10.1158/1078-0432.CCR-18-4175 Annotation 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. Workplace Institute of Computer Science Contact Tereza Šírová, sirova@cs.cas.cz, Tel.: 266 053 800 Year of Publishing 2020
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