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Gut epithelial Interleukin-17 receptor A signaling can modulate distant tumors growth through microbial regulation

2023; Cell Press; Volume: 42; Issue: 1 Linguagem: Inglês

10.1016/j.ccell.2023.12.006

1878-3686

Vidhi Chandra, Le Li, Olivereen Le Roux, Yu Zhang, Rian M. Howell, Dhwani N. Rupani, Seyda Baydogan, Haiyan D Miller, Erick Riquelme, Joseph F. Petrosino, Michael P. Kim, Krishna Bhat, James R. White, Jay K. Kolls, Yuliya Pylayeva‐Gupta, Florencia McAllister,

Psoriasis: Treatment and Pathogenesis

Microbes influence cancer initiation, progression and therapy responsiveness. IL-17 signaling contributes to gut barrier immunity by regulating microbes but also drives tumor growth. A knowledge gap remains regarding the influence of enteric IL-17-IL-17RA signaling and their microbial regulation on the behavior of distant tumors. We demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA induces growth of pancreatic and brain tumors due to excessive development of Th17, primary source of IL-17 in human and mouse pancreatic ductal adenocarcinoma, as well as B cells that circulate to distant tumors. Microbial dependent IL-17 signaling increases DUOX2 signaling in tumor cells. Inefficacy of pharmacological inhibition of IL-17RA is overcome with targeted microbial ablation that blocks the compensatory loop. These findings demonstrate the complexities of IL-17-IL-17RA signaling in different compartments and the relevance for accounting for its homeostatic host defense function during cancer therapy.