T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) elicits antitumor activity in various tumor models; however, the underlying mechanism of action remains unclear. Here we demonstrate a crucial role for interleukin (IL)-9 in antitumor immunity generated by the GITR agonistic antibody DTA-1. IL-4 receptor knockout (Il4ra−/−) mice, which have reduced expression of IL-9, were resistant to tumor growth inhibition by DTA-1. Notably, neutralization of IL-9 considerably impaired tumor rejection induced by DTA-1. In particular, DTA-1–induced IL-9 promoted tumor-specific cytotoxic T lymphocyte (CTL) responses by enhancing the function of dendritic cells in vivo. Furthermore, GITR signaling enhanced the differentiation of IL-9–producing CD4+ T-helper (TH9) cells in a TNFR-associated factor 6 (TRAF6)- and NF-κB–dependent manner and inhibited the generation of induced regulatory T cells in vitro. Our findings demonstrate that GITR co-stimulation mediates antitumor immunity by promoting TH9 cell differentiation and enhancing CTL responses and thus provide a mechanism of action for GITR agonist–mediated cancer immunotherapies.
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We thank J.-O. Kim (International Vaccine Institute) for CD45.1 congenic mice, D.H. Chung (Seoul National University College of Medicine) for IL-4–deficient mice, Y.-K. Kim (Ewha Institute of Convergence Medicine) for IL-4Ra–deficient mice, T.H. Watts (University of Toronto) and P.P. Pandolfi (Harvard Medical School) for GITR-deficient mice, C.D. Surh (Pohang University of Science and Technology) and T.A. Chatila (Harvard Medical School) for Foxp3GFP reporter mice, Y. Choi (University of Pennsylvania School of Medicine) for Traf6fl/fl mice, G. Lozano (MD Anderson Cancer Center) for K-Ras transgenic mice, S. Sakaguchi (Osaka University) for the antibody to GITR (DTA-1), J.v. Snick (Ludwig Institute) for the antibody to IL-9 (MM9C1), S.-I. Nishikawa (RIKEN Center for Developmental Biology) for the antibody to c-kit (ACK2), H.-W. Yum (Seoul National University) and D.-H. Kim (Seoul National University) for assistance in setting up a colorectal cancer model, and members of the Kang laboratory for technical support. This work was supported by grants from the Public Welfare & Safety Research Program (20100020843; C.-Y.K.) and the National R&D Program for Cancer Control, Ministry of Health and Welfare (no. 0720500; C.-Y.K.).
The authors declare no competing financial interests.
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Kim, I., Kim, B., Koh, C. et al. Glucocorticoid-induced tumor necrosis factor receptor–related protein co-stimulation facilitates tumor regression by inducing IL-9–producing helper T cells. Nat Med 21, 1010–1017 (2015) doi:10.1038/nm.3922
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