Adding a new wrinkle to the mechanism(s) of action of T cell-targeted immunomodulatory mAbs, Waight et al. demonstrate that engagement of the Fc portion of antibodies (such as those targeting the inhibitory receptors CTLA-4 and TIGIT on superantigen-stimulated T cells and the CD45RB isoform on Tregs) by FcγR on APCs significantly modulates the resulting T cell response. Human FcγRIIIA (and the comparable FcγRIV in mice) were the key receptors driving superior IL-2 production, and in humans, a CD11chi DC population was involved. The Fc/FcγR-mediated stimulation was shown to be independent of Treg depletion.
The co-engagement of fragment crystallizable (Fc) gamma receptors (FcgammaRs) with the Fc region of recombinant immunoglobulin monoclonal antibodies (mAbs) and its contribution to therapeutic activity has been extensively studied. For example, Fc-FcgammaR 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 FcgammaR co-engagement on antigen-presenting cells (APCs). In the case of mAbs targeting CTLA-4 and TIGIT, the interaction with FcgammaR on APCs enhanced antigen-specific T cell responses and tumoricidal activity. This mechanism extended to an anti-CD45RB mAb, which led to FcgammaR-dependent regulatory T cell expansion in mice.