Shah, M. (Mansi)

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    Anti-CTLA-4 antibodies drive myeloid activation and reprogram the tumor microenvironment through FcγR engagement and type I interferon signaling
    (Springer, 2022) Yofe, I. (Ido); Landsberger, T. (Tomer); Yalin, A. (Adam); Solomon, I. (Isabelle); Costoya, C. (Cristóbal); Franz-Demane, D. (Dafne); Shah, M. (Mansi); David, E. (Eyal); Borenstein, C. (Chamutal); Barboy, O. (Oren); Matos, I. (Ignacio); Peggs, K.S. (Karl S.); Quezada, S.A. (Sergio A.); Amit, I. (Ido)
    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 Fcγ receptor (FcγR)-dependent depletion of regulatory T cells (Treg) is critical for antitumor activity. Here, using single-cell RNA sequencing, we dissect the impact of anti-CTLA-4-blocking, Treg 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 Treg cell ablation models, we show that immune remodeling was not driven solely by Treg cell depletion or CTLA-4 blockade but mainly through FcγR engagement, downstream activation of type I interferon signaling and reduction of suppressive macrophages. Our findings indicate that FcγR engagement and innate immune remodeling are involved in successful anti-CTLA-4 treatment, supporting the development of optimized immunotherapy agents bearing these features.