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 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-gamma 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.
Teng
Michele W L
MW
Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
Andrews
Daniel M
DM
McLaughlin
Nicole
N
von Scheidt
Bianca
B
Ngiow
Shin Foong
SF
Möller
Andreas
A
Hill
Geoffrey R
GR
Iwakura
Yoichiro
Y
Oft
Martin
M
Smyth
Mark J
MJ
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D007113:Immunity, Innate; D007167:Immunotherapy; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology; D053760:Interleukin-23 Subunit p19 / Q000172:deficiency / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000276:immunology*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology*; D054353:Perforin / Q000276:immunology
C098680:Il17a protein, mouse; C508841:Il23a protein, mouse; D020381:Interleukin-17; D007376:Interleukin-2; D053760:Interleukin-23 Subunit p19; D054353:Perforin; D007371:Interferon-gamma
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