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Fucikova, Jitka; Rakova, Jana; Hensler, Michal; Kasikova, Lenka; Belicova, Lucie; Hladikova, Kamila; Truxova, Iva; Skapa, Petr; Laco, Jan; Pecen, Ladislav; Praznovec, Ivan; Halaska, Michael J.; Brtnicky, Tomas; Kodet, Roman; Fialova, Anna; Pineau, Josephine; Gey, Alain; Tartour, Eric; Ryska, Ales; Galluzzi, Lorenzo; Spisek, Radek

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

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  • Medientyp: E-Artikel
  • Titel: TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer
  • Beteiligte: Fucikova, Jitka; Rakova, Jana; Hensler, Michal; Kasikova, Lenka; Belicova, Lucie; Hladikova, Kamila; Truxova, Iva; Skapa, Petr; Laco, Jan; Pecen, Ladislav; Praznovec, Ivan; Halaska, Michael J.; Brtnicky, Tomas; Kodet, Roman; Fialova, Anna; Pineau, Josephine; Gey, Alain; Tartour, Eric; Ryska, Ales; Galluzzi, Lorenzo; Spisek, Radek
  • Erschienen: American Association for Cancer Research (AACR), 2019
  • Erschienen in: Clinical Cancer Research, 25 (2019) 15, Seite 4820-4831
  • Sprache: Englisch
  • DOI: 10.1158/1078-0432.ccr-18-4175
  • ISSN: 1078-0432; 1557-3265
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: Abstract 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. 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.
  • Zugangsstatus: Freier Zugang