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 [αCTLA-4]- and anti-PD-1 [αPD-1]-related colitis have been poorly described. The aim of the present study was to compare the immunological and histological characteristics of αCTLA-4-induced colitis and αPD-1-induced colitis. Methods: Colonic biopsies from patients with αCTLA-4-induced colitis, αPD-1-induced colitis, and inflammatory bowel disease [IBD] were analysed by immunohistochemistry and flow cytometry. Tumour necrosis factor alpha [TNFa] concentration was assessed in biopsy supernatants. Results: CD8⁺ T cells were found in the lamina propria and epithelium in αPD-1-induced colitis, whereas CD4⁺ T cells were found in the lamina propria in αCTLA-4-induced colitis. No or low intraepithelial lymphocytes were observed in αCTLA-4-induced colitis. No difference in numbers of mucosal regulatory T cells was observed between αCTLA-4- or αPD-1-induced colitis and IBD patients. Higher numbers of activated ICOS⁺ conventional CD4⁺ T cells were observed in αCTLA- 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 αCTLA-4-induced colitis, whereas Treg cells were predominant in IBD or αPD-1-induced colitis. High mucosal TNFa concentrations were observed in αCTLA-4-induced colitis. Low mucosal TNFa concentrations were associated with steroid sensitivity. Conclusions: These observations show that αCTLA-4- and αPD-1-induced colitis have distinct immunological characteristics. Mucosal TNFa concentration might detect patients at risk of developing corticosteroid resistance after CTLA-4 blockade.