| Autor: |
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. |
| Zdroj: |
The Journal of Experimental Medicine; February 2023, Vol. 220 Issue: 2 pe20221333-e20221333, 1p |
| Abstrakt: |
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. |
| Databáze: |
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