Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration Journal Article
| Authors: | Zhou, Y.; Medik, Y. B.; Patel, B.; Zamler, D. B.; Chen, S.; Chapman, T.; Schneider, S.; Park, E. M.; Babcock, R. L.; Chrisikos, T. T.; Kahn, L. M.; Dyevoich, A. M.; Pineda, J. E.; Wong, M. C.; Mishra, A. K.; Cass, S. H.; Cogdill, A. P.; Johnson, D. H.; Johnson, S. B.; Wani, K.; Ledesma, D. A.; Hudgens, C. W.; Wang, J.; Wadud Khan, M. A.; Peterson, C. B.; Joon, A. Y.; Peng, W.; Li, H. S.; Arora, R.; Tang, X.; Raso, M. G.; Zhang, X.; Foo, W. C.; Tetzlaff, M. T.; Diehl, G. E.; Clise-Dwyer, K.; Whitley, E. M.; Gubin, M. M.; Allison, J. P.; Hwu, P.; Ajami, N. J.; Diab, A.; Wargo, J. A.; Watowich, S. S. |
| Article Title: | Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration |
| 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. © 2022 Zhou et al. |
| Keywords: | mouse; animal; animals; mice; quality of life; inflammation; pathology; immunotherapy; interleukin 6; interleukin-6; colitis |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 220 |
| Issue: | 2 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2023-02-06 |
| Start Page: | e20221333 |
| Language: | English |
| DOI: | 10.1084/jem.20221333 |
| PUBMED: | 36367776 |
| PROVIDER: | scopus |
| PMCID: | PMC9664499 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2022 -- Source: Scopus |
