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.