Anti-CTLA-4 antibodies drive myeloid activation and reprogram the tumor microenvironment through Fc gamma R engagement and type I interferon signaling

Despite the clinical success of checkpoint inhibitors, a substantial gap still exists in our understanding of their mechanism of action. While antibodies to cytotoxic T lymphocyte-associated protein-4 (CTLA-4) were developed to block inhibitory signals in T cells, several recent studies have demonstrated that Fc gamma receptor (Fc gamma R)-dependent depletion of regulatory T cells (T-reg) is critical for antitumor activity. Here, using single-cell RNA sequencing, we dissect the impact of anti-CTLA-4-blocking, T-reg cell-depleting and FcR-engaging activity on the immune response within tumors. We observed a rapid remodeling of the innate immune landscape as early as 24 h after treatment. Using genetic T-reg cell ablation models, we show that immune remodeling was not driven solely by T-reg cell depletion or CTLA-4 blockade but mainly through Fc gamma R engagement, downstream activation of type I interferon signaling and reduction of suppressive macrophages. Our findings indicate that Fc gamma R engagement and innate immune remodeling are involved in successful anti-CTLA-4 treatment, supporting the development of optimized immunotherapy agents bearing these features.