IL-18 induces PD-1-dependent immunosuppression in cancer

Magali Terme, Evelyn Ullrich, Laetitia Aymeric, Kathrin Meinhardt, Mélanie Desbois, Nicolas Delahaye, Sophie Viaud, Bernard Ryffel, Hideo Yagita, Gilles Kaplanski, Armelle Prévost-Blondel, Masashi Kato, Joachim L. Schultze, Eric Tartour, Guido Kroemer, Nathalie Chaput, Laurence Zitvogel

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    300 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)5393-5399
    Number of pages7
    JournalCancer Research
    Volume71
    Issue number16
    DOIs
    Publication statusPublished - 15 Aug 2011

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