期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 49, 页码 12994-12999出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1705165114
关键词
interleukin-22; interleukin-1; inflammasome; cancer immunology; anakinra
资金
- Wilhelm Sander Stiftung [2014.018.1]
- International Doctoral Program i-Target: Immunotargeting of Cancer - Elite Network of Bavaria
- Melanoma Research Alliance [N269626, 409510]
- Marie-Sklodowska-Curie Program Training Network for the Immunotherapy of Cancer - European Union [641549]
- Else Kroner-Fresenius-Stiftung
- German Cancer Aid
- Ernst-Jung-Stiftung
- LMU Munich's Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative
- Bundesministerium fur Bildung und Forschung Project Oncoattract
- European Research Council [756017, 260524, 679345]
- Comprehensive Pneumology Center Research School Program Lung Biology and Disease
- Human Tissue and Cell Research, a nonprofit foundation under German civil law
- Marie Curie Actions (MSCA) [641549] Funding Source: Marie Curie Actions (MSCA)
IL-22 has been identified as a cancer-promoting cytokine that is secreted by infiltrating immune cells in several cancer models. We hypothesized that IL-22 regulation would occur at the interface between cancer cells and immune cells. Breast and lung cancer cells of murine and human origin induced IL-22 production from memory CD4(+) T cells. In the present study, we found that IL-22 production in humans is dependent on activation of the NLRP3 inflammasome with the subsequent release of IL-1 beta from both myeloid and T cells. IL-1 receptor signaling via the transcription factors AhR and ROR gamma t in T cells was necessary and sufficient for IL-22 production. In these settings, IL-1 induced IL-22 production from a mixed T helper cell population comprised of Th1, Th17, and Th22 cells, which was abrogated by the addition of anakinra. We confirmed these findings in vitro and in vivo in two murine tumor models, in primary human breast and lung cancer cells, and in deposited expression data. Relevant to ongoing clinical trials in breast cancer, we demonstrate here that the IL-1 receptor antagonist anakinra abrogates IL-22 production and reduces tumor growth in a murine breast cancer model. Thus, we describe here a previously unrecognized mechanism by which cancer cells induce IL-22 production from memory CD4(+) T cells via activation of the NLRP3 inflammasome and the release of IL-1 beta to promote tumor growth. These findings may provide the basis for therapeutic interventions that affect IL-22 production by targeting IL-1 activity.
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