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

Michele W L Teng, Daniel M. Andrews, Nicole M McLaughlin, Bianca von Scheidt, Shin Foong Ngiow, Andreas Möller, Geoffrey R Hill, Yoichiro Iwakura, Martin Oft, Mark J. Smyth

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84 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)8328-8333
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number18
DOIs
Publication statusPublished - 4 May 2010
Externally publishedYes

Keywords

  • IL-2
  • Inflammation
  • Innate immunity
  • NK cell
  • Tumor

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