title: IL-18 induces PD-1-dependent immunosuppression in cancer.
abstract: Immunosuppressive cytokines subvert innate and adaptive immune responses during cancer progression. The inflammatory cytokine interleukin-18 (IL-18) is known to accumulate in cancer patients, but its pathophysiological role remains unclear. In this study, we show that low levels of circulating IL-18, either exogenous or tumor derived, act to suppress the NK cell arm of tumor immunosurveillance. IL-18 produced by tumor cells promotes the development of NK-controlled metastases in a PD-1-dependent manner. Accordingly, PD-1 is expressed by activated mature NK cells in lymphoid organs of tumor bearers and is upregulated by IL-18. RNAi-mediated knockdown of IL-18 in tumors, or its systemic depletion by IL-18-binding protein, are sufficient to stimulate NK cell-dependent immunosurveillance in various tumor models. Together, these results define IL-18 as an immunosuppressive cytokine in cancer. Our findings suggest novel clinical implementations of anti-PD-1 antibodies in human malignancies that produce IL-18.
authors: Institut Gustave Roussy, Université Paris Descartes, Paris, France.
authors: Magali
authors: M
authors: Terme
authors: Evelyn
authors: E
authors: Ullrich
authors: Laetitia
authors: L
authors: Aymeric
authors: Kathrin
authors: K
authors: Meinhardt
authors: Mélanie
authors: M
authors: Desbois
authors: Nicolas
authors: N
authors: Delahaye
authors: Sophie
authors: S
authors: Viaud
authors: Bernard
authors: B
authors: Ryffel
authors: Hideo
authors: H
authors: Yagita
authors: Gilles
authors: G
authors: Kaplanski
authors: Armelle
authors: A
authors: Prévost-Blondel
authors: Masashi
authors: M
authors: Kato
authors: Joachim L
authors: JL
authors: Schultze
authors: Eric
authors: E
authors: Tartour
authors: Guido
authors: G
authors: Kroemer
authors: Nathalie
authors: N
authors: Chaput
authors: Laurence
authors: L
authors: Zitvogel
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000276:immunology / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000502:physiology*; D001323:Autoantibodies / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007108:Immune Tolerance; D020382:Interleukin-18 / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; D020382:Interleukin-18; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor