GITR Agonists Facilitate Antitumor Responses via T_H9 Cells and IL9

Glucocorticoid-induced TNF receptor–related protein (GITR, also known as TNFRSF18) stimulates antitumor responses via T-cell activation in a variety of animal cancer models, but the detailed mechanisms of its action are not well understood. Kim and colleagues found that the GITR-specific agonistic antibody DTA-1 suppressed tumor growth in a syngeneic mouse model of cancer, but not in IL4 receptor–deficient (Il4ra^−/−) mice. DTA-1–induced tumor regression was mediated by CD4⁺ T-cell–dependent production of IL9, which was absent in Il4ra^−/− mice. Furthermore, DTA-1–triggered IL9 expression increased the number and activity of tumor-specific CD8⁺ CTLs by enhancing the cross-presentation function of tumor-associated dendritic cells (DC) in vivo; these effects were reversed by treatment with a neutralizing antibody to IL9. CD4⁺ T-cell–driven production of IL9 was stimulated under T_H9-polarizing conditions in mouse cells treated with DTA-1 and in human cells treated with an agonist antibody to human GITR, demonstrating that GITR costimulation promotes the differentiation of T_H9 cells. In addition, GITR costimulation shifted the balance of induced regulatory T cells and T_H9 cells in favor of T_H9 differentiation both in vitro and in vivo. IL9 production in DTA-1–treated cells was increased even under IL4-abundant conditions, but was reduced by pretreatment with a chemical inhibitor of the NFκB pathway. Consistent with this finding, DTA-1 treatment upregulated expression of TNF receptor–associated factor 6 (TRAF6), a mediator of NFκB activation, and failed to increase IL9 production in TRAF6-deficient CD4⁺ T cells under T_H9-polarizing conditions. Taken together, these findings suggest that GITR costimulation promotes T_H9 cell differentiation and IL9 production via activation of the TRAF6–NFκB pathway and increased IL4 production, enhancing tumor-associated DC function and facilitating antitumor CTL responses. These findings elucidate the cellular and molecular mechanisms underlying the antitumor activity of GITR agonist immunotherapies and support clinical trials of GITR agonists to generate antitumor immune responses.

Kim IK, Kim BS, Koh CH, Seok JW, Park JS, Shin KS, 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 2015;21:1010–7.

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