FCγRIIIA and FCγRIIA Engagement Mediates Antitumor Cellular Immunity

Passive delivery of antitumor mAbs has been shown to promote rapid tumor cell death via transient induction of Fc-receptor for IgG (FcγR)–mediated antibody-dependent cellular cytotoxicity (ADCC), which is determined by the relative binding affinity of antibodies for activating and inhibitory FcγR receptors on effector cell surfaces. In addition, antitumor mAb therapy has also led to durable antitumor cellular immune responses in some patients, prompting DiLillo and Ravetch to study the mechanisms that underlie this long-term vaccinal effect. In a murine lymphoma model expressing the tumor neoantigen human CD20 (hCD20), treatment with the murine IgG2a isotype anti-hCD20 mAb led to rapid clearance of lymphoma cells via FcγR-mediated ADCC, as well as sustained antitumor immune responses when mice were subsequently rechallenged with tumor cells that expressed hCD20, but not cells lacking hCD20 expression. Mechanistically, CD11c⁺ cell–specific deletion of the activating receptor mFcγRIV revealed that expression of mFcγRIV was required to generate long-term mAb-stimulated vaccinal effects, but was dispensable for ADCC-mediated tumor cell killing. In order to bypass interspecies differences and assess the individual contributions of hFcγRs in generating mAb-induced antitumor responses, FcγR-humanized mice expressing hFcγRs in the absence of mFcγRs were treated with hIgG1 anti-hCD20 variants engineered to selectively engage hFcγRIIIA, hFcγRIIA, or both hFcγRIIIA and hFcγRIIA. Engagement of hFcγRIIIA, but not hFcγRIIA, was necessary and sufficient to promote ADCC-mediated primary tumor cell clearance via clodronate liposome–sensitive macrophages. In contrast, however, long-term vaccinal effects required hFcγRIIA expressed by dendritic cells. Together, this work highlights the role of differential FcγR engagement in primary and long-term mAb-mediated antitumor immune responses and suggests that targeting both FcγRIIIA and FcγRIIA may be required for maximal clinical benefit of antitumor antibodies.

DiLillo DJ, Ravetch JV. Differential Fc-receptor engagement drives an anti-tumor vaccinal effect. Cell 2015;161:1035–45.

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