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Glucocorticoid-induced tumor necrosis factor receptor-related protein co-stimulation facilitates tumor regression by inducing IL-9-producing helper T cells.

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.
AuthorsIl-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
JournalNature medicine (Nat Med) Vol. 21 Issue 9 Pg. 1010-7 (Sep 2015) ISSN: 1546-170X [Electronic] United States
PMID26280119 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Glucocorticoid-Induced TNFR-Related Protein
  • Glucocorticoids
  • Interleukin-9
  • NF-kappa B
  • Receptors, Interleukin-4
  • TNF Receptor-Associated Factor 6
  • Tnfrsf18 protein, mouse
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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