Clélia Coutzac1,2, Julien Adam3,4, Emilie Soularue1,2,5, Michael Collins2,5, Antoine Racine2,5, Charlotte Mussini6, Lisa Boselli1, Nyam Kamsukom7, Christine Mateus7, Mélinda Charrier1,2, Lydie Cassard1, David Planchard8, Vincent Ribrag9, Karim Fizazi2,10, Yohann Loriot10, Patricia Lepage11, Jean-Yves Scoazec2,3,4, Caroline Robert2,7, Franck Carbonnel2,5, Nathalie Chaput1,12. 1. Gustave Roussy, Laboratory d'Immunomonitoring en Oncologie, CNRS-UMS 3655 and INSERM-US23, Villejuif F-94805, France. 2. University Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre, F-94276, France. 3. Gustave Roussy, Department of Pathology and Laboratory Medicine [BIOpath], Villejuif F-94805, France. 4. Gustave Roussy, AMMICa, CNRS-UMS 3655 and INSERM-US23, Villejuif F-94805, France. 5. Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris [AP-HP], Le Kremlin Bicêtre, France. 6. Department of Pathology, Kremlin Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris [AP-HP], Le Kremlin Bicêtre, France. 7. Gustave Roussy, Département de Médecine, Service de Dermatologie, Villejuif, F-94805, France. 8. Gustave Roussy, Département de Médecine Oncologique, Service de pathologie thoracique, Villejuif, F-94805, France. 9. Gustave Roussy, Drug Development Department [DITEP]Villejuif F-94805, France. 10. Gustave Roussy Cancer Campus [GRCC], Department of Cancer Medicine, Villejuif F-94805, France. 11. Micalis Institute, INRA, AgroParisTech, University Paris-Saclay, 78350 Jouy-en-Josas, France. 12. University Paris-Sud, Faculté de Pharmacie, Chatenay-Malabry, Châtenay-Malabry, F-92 296, France.
Abstract
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 [TNFα] 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 TNFα concentrations were observed in αCTLA-4-induced colitis. Low mucosal TNFα concentrations were associated with steroid sensitivity. CONCLUSIONS: 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.
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 [TNFα] 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 TNFα concentrations were observed in αCTLA-4-induced colitis. Low mucosal TNFα concentrations were associated with steroid sensitivity. CONCLUSIONS: 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.
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