Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies

Fc gamma receptor (Fc gamma R) coengagement can facilitate antibody-mediated receptor activation in target cells. In particular, agonistic antibodies that target tumor necrosis factor receptor (TNFR) family members have shown dependence on expression of the inhibitory Fc gamma R, Fc gamma RIIB. It remains unclear if engagement of Fc gamma RIIB also extends to the activities of antibodies targeting immunoregulatory TNFRs expressed by T cells. We have explored the requirement for activating and inhibitory Fc gamma Rs for the antitumor effects of antibodies targeting the TNFR glucocorticoid-induced TNFR-related protein (GITR; TNFRSF18; CD357) expressed on activated and regulatory T cells (T reg cells). We found that although Fc gamma RIIB was dispensable for the in vivo efficacy of anti-GITR antibodies, in contrast, activating Fc gamma Rs were essential. Surprisingly, the dependence on activating Fc gamma Rs extended to an antibody targeting the non-TNFR receptor CTLA-4 (CD152) that acts as a negative regulator of T cell immunity. We define a common mechanism that correlated with tumor efficacy, whereby antibodies that coengaged activating Fc gamma Rs expressed by tumor-associated leukocytes facilitated the selective elimination of intratumoral T cell populations, particularly T reg cells. These findings may have broad implications for antibody engineering efforts aimed at enhancing the therapeutic activity of immunomodulatory antibodies.