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Clélia Coutzac, Julien Adam, Emilie Soularue, Michael Collins, Antoine Racine, Charlotte Mussini, Lisa Boselli, Nyam Kamsukom, Christine Mateus, Mélinda Charrier, Lydie Cassard, David Planchard, Vincent Ribrag, Karim Fizazi, Yohann Loriot, Patricia Lepage, Jean-Yves Scoazec, Caroline Robert, Franck Carbonnel, Nathalie Chaput, Colon Immune-Related Adverse Events: Anti-CTLA-4 and Anti-PD-1 Blockade Induce Distinct Immunopathological Entities, Journal of Crohn's and Colitis, Volume 11, Issue 10, October 2017, Pages 1238–1246, https://doi.org/10.1093/ecco-jcc/jjx081
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Abstract
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.
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 [TNFα] concentration was assessed in biopsy supernatants.
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 TNFα concentrations were observed in αCTLA-4-induced colitis. Low mucosal TNFα concentrations were associated with steroid sensitivity.
These observations show that αCTLA-4- and αPD-1-induced colitis have distinct immunological characteristics. Mucosal TNFα concentration might detect patients at risk of developing corticosteroid resistance after CTLA-4 blockade.
