Colon Immune-Related Adverse Events: Anti-CTLA-4 and Anti-PD-1 Blockade Induce Distinct Immunopathological Entities

Background and Aim: Immune checkpoint inhibitors targeting CTLA-4 and PD-1 improve survival in cancer patients but may induce immune-related adverse events, including colitis. The immunological characteristics of anti-CTLA-4 [alpha CTLA-4]- and anti-PD-1 [alpha PD-1]-related colitis have been poorly described. The aim of the present study was to compare the immunological and histological characteristics of alpha CTLA-4-induced colitis and alpha PD-1-induced colitis. Methods: Colonic biopsies from patients with alpha CTLA-4-induced colitis, alpha PD-1-induced colitis, and inflammatory bowel disease [IBD] were analysed by immunohistochemistry and flow cytometry. Tumour necrosis factor alpha [TNF alpha] concentration was assessed in biopsy supernatants. Results: CD8(+) T cells were found in the lamina propria and epithelium in alpha PD-1-induced colitis, whereas CD4(+) T cells were found in the lamina propria in alpha CTLA-4-induced colitis. No or low intraepithelial lymphocytes were observed in alpha CTLA-4-induced colitis. No difference in numbers of mucosal regulatory T cells was observed between alpha CTLA-4- or alpha PD-1-induced colitis and IBD patients. Higher numbers of activated ICOS+ conventional CD4(+) T cells were observed in alpha CTLA-4- induced colitis compared with patients with IBD. Among ICOS+ CD4(+) T cells, conventional CD4(+) T cells were the main T cell population in patents with alpha CTLA-4-induced colitis, whereas Treg cells were predominant in IBD or alpha PD-1-induced colitis. High mucosal TNF alpha concentrations were observed in alpha CTLA-4-induced colitis. Low mucosal TNF alpha concentrations were associated with steroid sensitivity. Conclusions: These observations show that alpha CTLA-4- and alpha PD-1-induced colitis have distinct immunological characteristics. Mucosal TNF alpha concentration might detect patients at risk of developing corticosteroid resistance after CTLA-4 blockade.