IL-18 Induces PD-1–Dependent Immunosuppression in Cancer
2011; American Association for Cancer Research; Volume: 71; Issue: 16 Linguagem: Inglês
10.1158/0008-5472.can-11-0993
ISSN1538-7445
AutoresMagali 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, Éric Tartour, Guido Kroemer, Nathalie Chaput, Laurence Zitvogel,
Tópico(s)Immunotherapy and Immune Responses
ResumoAbstract 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. Cancer Res; 71(16); 5393–9. ©2011 AACR.
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