OX86 mediates depletion of OX40-expressing intratumoral regulatory T cells through Fc receptor co-engagement, leading to potent anti-tumor efficacy

Antibodies targeting T cell receptors have shown remarkable antitumor efficacy in preclinical and clinical studies. The engagement of activating Fc receptor (FcR)-expressing immune cells was recently shown to mediate the tumoricidal efficacy of antibodies recognizing GITR and CTLA-4. Activating FcRs facilitated the selective elimination of intratumoral T cell populations. However, it remains unclear whether FcRs contribute to the antitumor efficacy of other well-known surrogate immunomodulatory antibodies. To extend this thesis, we explored the mechanism of antitumor activity mediated by an anti-OX40 antibody (clone OX86). Like GITR and CTLA-4, OX40 was highly expressed by intratumoral T cells, particularly those of the regulatory T cell lineage. OX86 administration resulted in the strong depletion of intratumoral regulatory T cells in an activating-FcR dependent manner, which also correlated with tumor regression. We propose a paradigm, whereby antibodies targeting antigens highly expressed on intratumoral T cells leads to their elimination by FcR-expressing immune cells, which promotes antitumor immunity.