Autoantibodies Drive Fcγ Receptor-Dependent Colon Inflammation During Immune Checkpoint Blockade

Immune-related adverse events (irAEs), particularly colitis, are major limitations of immune checkpoint inhibitor (ICI) therapy, but their mechanisms remain poorly understood. Here we show that endogenous autoantibodies (AAbs) can promote ICI-associated colitis through Fcγ receptor-dependent pathways. IgG from melanoma patients treated with pembrolizumab, nivolumab, or ipilimumab, with or without severe colitis, was transferred into wild-type or humanized FcγR (hFcγR) mice receiving comparable ICI therapy. Wild-type mice did not develop changes in the colon. In contrast, hFcγR mice given IgG from patients with colitis developed colon inflammation marked by a significant increase in submucosal lymphocyte infiltration, goblet cell loss, and circulating cytokines, including IL-1β, IL-17a, and IL-22. Single-cell RNA sequencing identified an IgG-regulated inflammatory network involving IFNγ-producing ILC1, Th1 and cytotoxic T cells, IL-1β+ M1 macrophages, plasma B cells/plasmablasts, and IL-22-producing ILC3-LTi cells. Patient serum autoantibody profiling further identified CCR5 and CXCR4 receptors as candidate immune-related targets associated with ICC susceptibility. Immune-related adverse events (irAEs), particularly colitis, are major limitations of immune checkpoint inhibitor (ICI) therapy, but their mechanisms remain poorly understood. Here we show that endogenous autoantibodies (AAbs) can promote ICI-associated colitis through Fc gamma receptor (FcgR)-dependent pathways. IgG from melanoma patients treated with pembrolizumab, nivolumab, or ipilimumab, with or without severe colitis, was transferred into wild-type or humanized FcgR (hFcgR) mice receiving comparable ICI therapy. Wild-type mice did not develop changes in the colon. In contrast, hFcgR mice given IgG from patients with colitis developed colon inflammation marked by a significant increase in submucosal lymphocyte infiltration, goblet cell loss, and circulating cytokines, including IL-6, IL-17, and IL-22. Single-cell RNA sequencing identified an IgG-regulated inflammatory network involving IFNg-producing ILC1, Th1 and cytotoxic T cells, IL-1betta-M1 macrophages, plasma B cells/plasmablasts, and IL-22-producing ILC3-LTi cells. Patient serum autoantibody profiling further identified CCR5 and CXCR4 receptors as candidate immune-related targets associated with ICC susceptibility.