IL-18 Induces PD-1–Dependent Immunosuppression in Cancer
Published version of a preprint
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. Cancer Res; 71(16); 5393–9. ©2011 AACR.
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Multiple circulating cytokines and chemokines decreased after FMT in responders, including CCL2, CXCL8, IL-18, IL-12p70, and IFN-γ.
“Multiple circulating cytokines and chemokines decreased after FMT in Rs, including CCL2 (MCP1), CXCL8 (IL-8), and IL-18 that have been associated with negative outcomes to anti–PD-1 (32, 33), and IL-12p70 and IFN-γ (Fig. 4A, heatmap).”
From Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients (2021) · cites this paper as [33]
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- Authors
- Terme, M., Ullrich, E., Aymeric, L., Meinhardt, K., Desbois, M., Delahaye, N., Viaud, S., Ryffel, B., Yagita, H., Kaplanski, G., Prévost-Blondel, A., Kato, M., Schultze, J. L., Tartour, E., Kroemer, G., Chaput, N., & Zitvogel, L.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Authors' Affiliations: 1Institut Gustave Roussy; 2INSERM, U1015; 3INSERM, U848; 4Center of Clinical Investigations CBT507, Biotherapy, Villejuif; 5INSERM U970 PARCC, Université Paris Descartes; 6Institut Cochin, Université Paris Descartes, CNRS (UMR 8104); 7Inserm, U1016; 8Faculté Paris Sud-Université Paris XI, Paris; 9CNRS, IEM 2815, Institut Transgénose, Orléans; 10Service de Médecine Interne, Hôpital de la Conception, Marseille, France; 11Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nürnberg, Erlangen; 12Laboratory for Genomics and Immunoregulation, LIMES, University of Bonn, Bonn, Germany; 13Department of Immunology, Juntendo University School of Medicine, Tokyo; and 14Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi, Japan
- Corresponding author
- Zitvogel, Laurence
- ORCID
- Venue
- Cancer Research
- Published
- 2011-08-11
- Volume
- 71
- Issue
- 16
- Pages
- 5393-5399
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2115536507
- Cited by
- 376
- References
- 30
- Citations by year
- 2026: 10 · 2025: 26 · 2024: 16 · 2023: 32 · 2022: 23 · 2021: 28 · 2020: 39 · 2019: 27 · 2018: 22 · 2017: 34 · 2016: 37 · 2015: 24 · 2014: 25 · 2013: 18 · 2012: 15
- FWCI
- 8.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (23650241, 22240089)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- IL-18, PD-1, natural killer cells, tumor surveillance, immunosuppression, metastasis, anti-PD-1, IL-18 binding protein, tumor-derived cytokines, cancer immunotherapy
- MeSH terms
- Animals, Antigens, Surface, Autoantibodies, Enzyme-Linked Immunosorbent Assay, Female, Immune Tolerance, Killer Cells, Natural, Melanoma, Experimental, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasm Metastasis, Interleukin-18, Apoptosis Regulatory Proteins, Mice, Programmed Cell Death 1 Receptor
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