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SUMMARY The co-engagement of fragment crystallizable (Fc) gamma receptors (FcγRs) with the Fc region of recombinant immunoglobulin monoclonal antibodies (mAbs) and its contribution to therapeutic activity has been extensively studied. For example, Fc-FcγR interactions have been shown to be important for mAb-directed effector cell activities, as well as mAb-dependent forward signaling into target cells via receptor clustering. Here we identify a function of mAbs targeting T cell-expressed antigens that involves FcγR co-engagement on antigen-presenting cells (APCs). In the case of mAbs targeting CTLA-4 and TIGIT, the interaction with FcγR on APCs enhanced antigen-specific T cell responses and tumoricidal activity. This mechanism extended to an anti-CD45RB mAb, which led to FcγR-dependent regulatory T cell expansion in mice.

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Conflict of interest: VAA and AMS are authors of a patent filed by Northwestern University related to predicting the response to immunotherapy in gliomas (US2021071138). AMS has received in-kind and/or funding support for research from Agenus, Bristol Myers Squibb, and Carthera. RS has acted or is acting as a scientific advisor or has served on advisory boards for Alpheus Medical (formerly Craniovation), AstraZeneca, Boston Scientific, Carthera, Celularity, GT Medical, Insightech, Lockwood (BlackDiamond), Northwest Biotherapeutics, Novocure, Syneos Health (Boston Biomedical), TriAct Therapeutics, and Varian Medical Systems. ABH serves on the advisory board of Caris Life Sciences and the WCG Oncology Advisory Board; receives royalty and milestone payments from DNAtrix for the licensing of "Biomarkers and combination therapies using oncolytic virus and immunomodulation" (patent 11,065,285); and is supported by research grants from Celu larity, Codiak BioSciences, and AbbVie. She additionally has active granted patents for "miRNA for treating cancer and for use with adoptive immunotherapies" (patent 9,675,633) and "Concurrent chemotherapy and immuno therapy" (patent 9,399,662), with a patent pending for "Low intensity ultrasound combination cancer therapies" (international applications PCT/US2022/019435 and US 63/158,642).