| First Author | Zhou Y | Year | 2023 |
| Journal | J Exp Med | Volume | 220 |
| Issue | 2 | PubMed ID | 36367776 |
| Mgi Jnum | J:335587 | Mgi Id | MGI:7481884 |
| Doi | 10.1084/jem.20221333 | Citation | Zhou Y, et al. (2023) Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration. J Exp Med 220(2) |
| abstractText | Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (alphaCTLA-4)-mediated toxicity upon disruption of gut homeostatic immunity. We found alphaCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of alphaCTLA-4-mediated irAEs, including colonic neutrophil accumulation and systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved alphaCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of alphaCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs. |
