Glucocorticoid-induced tumor necrosis factor receptor-related protein co-stimulation facilitates tumor regression by inducing IL-9-producing helper T cells.
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.
Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Il-Kyu
IK
Kim
Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Byung-Seok
BS
Kim
Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Choong-Hyun
CH
Koh
Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
Jae-Won
JW
Seok
Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
Jun-Seok
JS
Park
Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Kwang-Soo
KS
Shin
Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
Eun-Ah
EA
Bae
Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Ga-Eun
GE
Lee
Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
Hyewon
H
Jeon
Laboratory of Pathophysiology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Jaebeom
J
Cho
Laboratory of Pathophysiology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Yujin
Y
Jung
Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, Republic of Korea.
Daehee
D
Han
Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea.
Byoung S
BS
Kwon
Laboratory of Pathophysiology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Ho-Young
HY
Lee
Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.|Center for Immunology and Autoimmune Diseases, Institute of Molecular Medicine, University of Texas Medical School at Houston, Houston, Texas, USA.
Yeonseok
Y
Chung
Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.|Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
Chang-Yuil
CY
Kang
D000818:Animals; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000502:physiology; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000502:physiology*; D005938:Glucocorticoids / Q000494:pharmacology*; D016906:Interleukin-9 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology*; D019948:Receptors, Interleukin-4 / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6 / Q000502:physiology
D053450:Glucocorticoid-Induced TNFR-Related Protein; D005938:Glucocorticoids; D016906:Interleukin-9; D016328:NF-kappa B; D019948:Receptors, Interleukin-4; D048029:TNF Receptor-Associated Factor 6; C106544:Tnfrsf18 protein, mouse