학술논문
Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration
Document Type
Article
Author
Zhou, Yifan; Medik, Yusra B.; Patel, Bhakti; Zamler, Daniel B.; Chen, Sijie; Chapman, Thomas; Schneider, Sarah; Park, Elizabeth M.; Babcock, Rachel L.; Chrisikos, Taylor T.; Kahn, Laura M.; Dyevoich, Allison M.; Pineda, Josue E.; Wong, Matthew C.; Mishra, Aditya K.; Cass, Samuel H.; Cogdill, Alexandria P.; Johnson, Daniel H.; Johnson, Sarah B.; Wani, Khalida; Ledesma, Debora A.; Hudgens, Courtney W.; Wang, Jingjing; Wadud Khan, Md Abdul; Peterson, Christine B.; Joon, Aron Y.; Peng, Weiyi; Li, Haiyan S.; Arora, Reetakshi; Tang, Ximing; Raso, Maria Gabriela; Zhang, Xuegong; Foo, Wai Chin; Tetzlaff, Michael T.; Diehl, Gretchen E.; Clise-Dwyer, Karen; Whitley, Elizabeth M.; Gubin, Matthew M.; Allison, James P.; Hwu, Patrick; Ajami, Nadim J.; Diab, Adi; Wargo, Jennifer A.; Watowich, Stephanie S.
Source
The Journal of Experimental Medicine; February 2023, Vol. 220 Issue: 2 pe20221333-e20221333, 1p
Subject
Language
ISSN
00221007; 15409538
Abstract
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 (αCTLA-4)–mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-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 αCTLA-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 αCTLA-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 αCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.