Autoantibodies Drive Fc Gamma Receptor-Dependent Colon Inflammation During Immune Checkpoint Blockade

Abstract

Immune checkpoint inhibitor (ICI)-associated colitis limits effective cancer immunotherapy, yet host determinants of severe toxicity remain undefined. We investigated whether humoral immunity is associated with subsequent severe immune-related colitis (irC). In melanoma patients, baseline serum autoantibody (AAb) profiling identified a composite antigen signature - a signature-level association rather than validated functional specificities - associated with severe irC, marked by retained reactivity to tumor-associated antigens and relative depletion of antibodies recognizing immune- and mucosal-regulatory proteins. To assess functional relevance, we transferred polyclonal IgG from severe- or non-severe-irC patients into wild-type or humanized Fc{gamma} receptor (hFc{gamma}R) mice treated with anti-PD-1 or anti-CTLA-4. IgG alone did not induce inflammation; however, severe-irC IgG amplified checkpoint-driven colonic inflammation in hFc{gamma}R mice, but not in wild-type mice, with checkpoint-specific remodeling of myeloid, lymphoid, and innate lymphoid compartments. These findings suggest that pretreatment humoral immunity conditions susceptibility to irC via the IgG-Fc{gamma}R axis.