Yofe, Landsberger, Yalin, et al. used scRNAseq and genetic mouse models to compare the antitumor mechanisms of two different CD80/86-blocking anti-CTLA-4 antibodies: anti-CTLA-4m2A (binds FcγR and depletes Tregs) and anti-CTLA-4m1 (binds FcγR, but incapable of depleting Tregs). Rapid, pronounced TME remodeling was only observed after anti-CTLA-4m2A treatment, resulting in depletion of CTLA-4high Tregs, but also accumulation of type1 IFN gene-expressing TAMs and Cxcr6+CD4+ T cells. Immune remodeling was independent of Treg depletion and mainly dependent on FcγR engagement driving type1 IFN signaling and reduced numbers of suppressive macrophages.
Contributed by Katherine Turner
ABSTRACT: 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.
Author Info: (1) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (3) Depa
Author Info: (1) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (3) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (4) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. (5) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. (6) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. (7) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. (8) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (9) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (10) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (11) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. (12) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. (13) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. s.quezada@ucl.ac.uk. (14) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. ido.amit@weizmann.ac.il.
