IL-23 suppresses innate immune response independently of IL-17A during carcinogenesis and metastasis
Michele W. L. Tenga,b, Daniel M. Andrewsa, Nicole McLaughlina, Bianca von Scheidta, Shin Foong Ngiowa,b, Andreas Möllerb,c, Geoffrey R. Hilld, Yoichiro Iwakurae, Martin Oftf, and Mark J. Smytha,b,1
- Author Affiliations
aCancer Immunology Program and
cCancer Genomics and Biochemistry Laboratory, Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia;
bDepartment of Pathology, University of Melbourne, Parkville 3010, Australia;
dQueensland Institute of Medical Research, Queensland 4006, Australia;
eDivision of Cell Biology, Centre for Experimental Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; and
fSchering–Plough BioPharma, Palo Alto, CA 94304
Edited* by James P. Allison, Memorial Sloan–Kettering Cancer Center, New York, NY, and approved March 17, 2010 (received for review March 12, 2010)
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-? 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.
pnas.org
Published online before print April 19, 2010, doi: 10.1073/pnas.1003251107
PNAS May 4, 2010 vol. 107 no. 18 8328-8333 |
