Journal
CANCER RESEARCH
Volume 71, Issue 16, Pages 5393-5399Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-11-0993
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Funding
- INCa
- ANR
- Ligue contre le cancer
- INFLACARE EU
- Canceropole IDF
- Ligue Nationale Contre le Cancer
- German Research Foundation (DFG)
- Fondation pour la Recherche Medicale (FRM)
- German Cancer Aid
- Deutscher Akademischer Austauschdienst (DAAD)
- Institut National du Cancer (INCa)
- Grants-in-Aid for Scientific Research [23650241, 22240089] Funding Source: KAKEN
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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. (c) 2011 AACR.
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