Abstract |
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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Authors | Il-Kyu Kim, Byung-Seok Kim, Choong-Hyun Koh, Jae-Won Seok, Jun-Seok Park, Kwang-Soo Shin, Eun-Ah Bae, Ga-Eun Lee, Hyewon Jeon, Jaebeom Cho, Yujin Jung, Daehee Han, Byoung S Kwon, Ho-Young Lee, Yeonseok Chung, Chang-Yuil Kang |
Journal | Nature medicine
(Nat Med)
Vol. 21
Issue 9
Pg. 1010-7
(Sep 2015)
ISSN: 1546-170X [Electronic] United States |
PMID | 26280119
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Glucocorticoid-Induced TNFR-Related Protein
- Glucocorticoids
- Interleukin-9
- NF-kappa B
- Receptors, Interleukin-4
- TNF Receptor-Associated Factor 6
- Tnfrsf18 protein, mouse
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Topics |
- Animals
- Cell Differentiation
- Dendritic Cells
(physiology)
- Glucocorticoid-Induced TNFR-Related Protein
(physiology)
- Glucocorticoids
(pharmacology)
- Interleukin-9
(physiology)
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- NF-kappa B
(physiology)
- Neoplasms, Experimental
(drug therapy, immunology)
- Receptors, Interleukin-4
(physiology)
- T-Lymphocytes, Cytotoxic
(immunology)
- T-Lymphocytes, Helper-Inducer
(immunology)
- T-Lymphocytes, Regulatory
(immunology)
- TNF Receptor-Associated Factor 6
(physiology)
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