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Pivotal Roles of CD4⁺ Effector T cells in Mediating Agonistic Anti-GITR mAb-Induced-Immune Activation and Tumor Immunity in CT26 Tumors

Discovery Research, Schering-Plough Biopharma (Formerly DNAX Research Institute), Palo Alto, CA 94304-1104

Glucocorticoid-induced TNF receptor family related protein (GITR) is a member of the TNFR superfamily. Previous studies have shown that in vivo administration of a GITR agonistic Ab (DTA-1) is able to overcome tolerance and induce tumor rejection in several murine syngeneic tumor models. However, little is known about the in vivo targets and the mechanisms of how this tolerance is overcome in a tumor-bearing host, nor is much known about how the immune network is regulated to achieve this antitumor response. In this study, we demonstrate that the in vivo ligation of GITR on CD4⁺ effector T cells renders them refractory to suppression by regulatory T (T_reg) cells in the CT26 tumor-bearing mouse. GITR engagement on T_reg cells does not appear to directly abrogate their suppressive function; rather, it increases the expansion of T_reg cells and promotes IL-10 production, a cytokine important for their suppressive function. Moreover, CD4⁺ effector T cells play a crucial role in mediating DTA-1-induced immune activation and expansion of CD8⁺, NK, and B cells in the tumor-draining lymph nodes. This includes increased CD69 expression on all of these subsets. In addition, NK and tumor-specific CD8⁺ T cells are generated that are cytolytic, which show increased intracellular IFN- production and CD107a mobilization, the latter a hallmark of cytolytic activities that lead to tumor killing.

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¹ Address correspondence and reprint requests to Dr. Xiao Min Schebye, Schering-Plough Biopharma, 901 California Avenue, Palo Alto, CA 94304. E-mail address: xiaomin.schebye{at}spcorp.com

² Abbreviations used in this paper: T_reg^, regulatory T cell; GITR, glucocorticoid-induced TNF receptor family related gene; TDLN, tumor draining lymph node.