Antibodies that coengage activating FcγRs expressed by tumor-associated leukocytes facilitate the selective elimination of intratumoral T cells.

Inhibitory FcγRIIB receptors are required for the therapeutic effects of agonistic antibodies targeting several tumor necrosis factor receptor (TNFR) superfamily members, including CD40, DR5, and Fas. However, it remains unclear how general this requirement is and whether activating FcγRs may be required for antibodies targeting other immunoregulatory receptors. Here we have explored the involvement of FcγRs for the antitumor effects of antibodies targeted to costimulatory TNFRs expressed on T cells. Surprisingly, FcγRIIB was completely dispensable for antibody-mediated anti-tumor effects. In contrast, activating FcγRs were required for maximal in vivo activity. A similar dependence on activating FcγRs was observed for antibodies targeted to the T cell surface antigen CTLA-4. Important changes in the tumor microenvironment and draining lymph nodes correlated with the in vivo efficacy of these antibodies. Our findings uncover a previously unknown requirement for activating FcγRs in the anti-tumor effects of immunomodulatory antibodies and raise important questions about the role of receptor signaling for therapeutic activity. A greater understanding of this activatory FcγR-based mechanism may improve the design and activity of immune-modulatory antibodies in clinical development, and those already approved for the clinic. Citation Format: Yannick Bulliard, Rose Jolicoeur, Maurice Windman, Sarah Rue, Deborah Knee, Nick Wilson, Glenn Dranoff, Jennifer Brogdon. Engagement of activatory Fc γ receptors by immunoregulatory receptor-targeting antibodies mediates antitumor activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 497. doi:10.1158/1538-7445.AM2013-497