Abstract & Authors:展开
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.
Stephanie S Watowich
Yifan Zhou,Yusra B Medik,Bhakti Patel,Daniel B Zamler,Sijie Chen,Thomas Chapman,Sarah Schneider,Elizabeth M Park,Rachel L Babcock,Taylor T Chrisikos,Laura M Kahn,Allison M Dyevoich,Josue E Pineda,Matthew C Wong,Aditya K Mishra,Samuel H Cass,Alexandria P Cogdill,Daniel H Johnson,Sarah B Johnson,Khalida Wani,Debora A Ledesma,Courtney W Hudgens,Jingjing Wang,Md Abdul Wadud Khan,Christine B Peterson,Aron Y Joon,Weiyi Peng,Haiyan S Li,Reetakshi Arora,Ximing Tang,Maria Gabriela Raso,Xuegong Zhang,Wai Chin Foo,Michael T Tetzlaff,Gretchen E Diehl,Karen Clise-Dwyer,Elizabeth M Whitley,Matthew M Gubin,James P Allison,Patrick Hwu,Nadim J Ajami,Adi Diab,Jennifer A Wargo,Stephanie S Watowich