IL-23 suppresses innate immune response independently of IL-17A during carcinogenesis and metastasis

IL-23 is an important molecular driver of Th17 cells and has strong tumor-promoting proinflammatory activity postulated to occur via adaptive immunity. Conversely, more recently it has been reported that IL-17A elicits a protective inflammation that promotes the activation of tumor-specific CD8⁺ T c...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2010-05, Vol.107 (18), p.8328-8333
Main Authors: Teng, Michele W.L, Andrews, Daniel M, McLaughlin, Nicole, von Scheidt, Bianca, Ngiow, Shin Foong, Möller, Andreas, Hill, Geoffrey R, Iwakura, Yoichiro, Oft, Martin, Smyth, Mark J
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Cancer
Carcinogens
Cell Line, Tumor
Cells
Cytokines
Female
Immune system
Immunity
Immunity, Innate
Immunotherapy
Innate immunity
Inoculation
Interferon-gamma - immunology
Interleukin-17 - immunology
Interleukin-2 - immunology
Interleukin-23 Subunit p19 - deficiency
Interleukin-23 Subunit p19 - immunology
Killer Cells, Natural - immunology
Lungs
Male
Metastasis
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocardium - immunology
Natural killer cells
Neoplasm Metastasis
Neoplasms - immunology
Neoplasms - pathology
Papilloma
Perforin - immunology
Rodents
T lymphocytes
Tumors
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Summary:IL-23 is an important molecular driver of Th17 cells and has strong tumor-promoting proinflammatory activity postulated to occur via adaptive immunity. Conversely, more recently it has been reported that IL-17A elicits a protective inflammation that promotes the activation of tumor-specific CD8⁺ T cells. Here we show the much broader impact of IL-23 in antagonizing antitumor immune responses primarily mediated by innate immunity. Furthermore, the majority of this impact was independent of IL-17A, which did not appear critical for many host responses to tumor initiation or metastases. IL-23-deficient mice were resistant to experimental tumor metastases in three models where host NK cells controlled disease. Immunotherapy with IL-2 was more effective in mice lacking IL-23, and again the protection afforded was NK cell mediated and independent of IL-17A. Further investigation revealed that loss of IL-23 promoted perforin and IFN-γ antitumor effector function in both metastasis models examined. IL-23-deficiency also strikingly protected mice from tumor formation in two distinct mouse models of carcinogenesis where the dependence on host IL-12p40 and IL-17A was quite different. Notably, in the 3'-methylcholanthrene (MCA) induction of fibrosarcoma model, this protection was completely lost in the absence of NK cells. Overall, these data indicate the general role that IL-23 plays in suppressing natural or cytokine-induced innate immunity, promoting tumor development and metastases independently of IL-17A.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1003251107