Deep immune phenotyping reveals distinct immunopathogenesis in checkpoint inhibitor-induced colitis compared to ulcerative colitis

Abstract Although initially assumed to be similar, immune checkpoint inhibitor (ICI)-induced autoimmunity can differ from spontaneous autoimmune disease regarding clinical presentation, pathogenesis and therapy. Despite limited pathogenetic understanding, ICI-induced colitis (irColitis), a common adverse event during ICI therapy, is treated analogously to its autoimmune counterpart, ulcerative colitis (UC). Thus, there is a tremendous need to characterize immunophenotypes in both forms of colonic inflammation to ultimately identify specific therapeutic strategies. In a multicenter study, local and systemic immunophenotypes of patients with irColitis were compared to patients with UC. Colonic mucosa, patient serum and peripheral blood mononuclear cells (PBMC) of 20 patients with irColitis, 15 patients with UC and 25 patients receiving ICI without toxicity were investigated. Immunophenotyping was performed using gene expression analyses of mucosal samples and PBMC, serum proteomics and flow cytometry-based PBMC analysis. Mucosal gene expression analysis revealed higher expression of B cell- and TNF signaling-related genes in UC, whereas irColitis mucosa showed an upregulation of genes associated with effector T cell responses and interferon signaling. Immunophenotyping of PBMC demonstrated increased activation and differentiation of T cells and higher expression of exhaustion markers in irColitis compared to UC. In contrast, dendritic cells (DC) and B cells demonstrated increased markers of activation in patients with UC. Taken together, irColitis is characterized by T cell-associated immunity, whereas B cell- and DC-mediated immune responses and TNF signaling are more important for UC immunopathogenesis. These observations could help identify more specific and efficient treatment strategies for irColitis.