title: Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies.
abstract: Fc γ receptor (FcγR) 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 FcγR, FcγRIIB. It remains unclear if engagement of FcγRIIB also extends to the activities of antibodies targeting immunoregulatory TNFRs expressed by T cells. We have explored the requirement for activating and inhibitory FcγRs 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 FcγRIIB was dispensable for the in vivo efficacy of anti-GITR antibodies, in contrast, activating FcγRs were essential. Surprisingly, the dependence on activating FcγRs 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 FcγRs 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.
authors.affiliation: Department of Oncology and 2 Laboratory Animal Services, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Bulliard
authors.forename: Rose
authors.initials: R
authors.lastname: Jolicoeur
authors.forename: Maurice
authors.initials: M
authors.lastname: Windman
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Rue
authors.forename: Seth
authors.initials: S
authors.lastname: Ettenberg
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Knee
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Wilson
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Brogdon
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D060908:CTLA-4 Antigen / Q000378:metabolism; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007155:Immunologic Factors / Q000494:pharmacology*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D017452:Receptors, IgG / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism
chemical_list: D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007155:Immunologic Factors; D017452:Receptors, IgG; C106544:Tnfrsf18 protein, mouse
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