Peggs, K.S. (Karl S.)

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    Fcγ receptors and immunomodulatory antibodies in cancer
    (Springer, 2024) Galvez-Cancino, F. (Felipe); Simpson, A.P. (Alexander P.); Costoya, C. (Cristóbal); Matos, I. (Ignacio); Qian, D. (Danwen); Peggs, K.S. (Karl S.); Litchfield, K. (Kevin); Quezada, S.A. (Sergio A.)
    The discovery of both cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) as negative regulators of antitumour immunity led to the development of numerous immunomodulatory antibodies as cancer treatments. Preclinical studies have demonstrated that the efficacy of immunoglobulin G (IgG)-based therapies depends not only on their ability to block or engage their targets but also on the antibody’s constant region (Fc) and its interactions with Fcγ receptors (FcγRs). Fc–FcγR interactions are essential for the activity of tumour-targeting antibodies, such as rituximab, trastuzumab and cetuximab, where the killing of tumour cells occurs at least in part due to these mechanisms. However, our understanding of these interactions in the context of immunomodulatory antibodies designed to boost antitumour immunity remains less explored. In this Review, we discuss our current understanding of the contribution of FcγRs to the in vivo activity of immunomodulatory antibodies and the challenges of translating results from preclinical models into the clinic. In addition, we review the impact of genetic variability of human FcγRs on the activity of therapeutic antibodies and how antibody engineering is being utilized to develop the next generation of cancer immunotherapies.
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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.