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

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

TLDR

  • The study found that gut bacteria can affect the way our bodies fight cancer. The study used mice to show that when the gut bacteria are out of balance, it can lead to the growth of pancreatic and brain tumors. The study also found that the gut bacteria can affect the way our bodies make a protein called IL-17, which is important for fighting cancer. The study suggests that targeting the gut bacteria could be a way to improve the effectiveness of cancer treatments.

Abstract

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.

Overview

  • The study investigates the influence of IL-17 signaling on cancer initiation, progression, and therapy responsiveness, with a focus on the gut microbiome and its regulation of IL-17-IL-17RA signaling. The study uses a mouse model to demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA leads to growth of pancreatic and brain tumors. The study also identifies the primary source of IL-17 in human and mouse pancreatic ductal adenocarcinoma as Th17 cells and circulating B cells that contribute to tumor growth. The study highlights the complexities of IL-17-IL-17RA signaling in different compartments and its relevance for accounting for its homeostatic host defense function during cancer therapy.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions, specifically the effects of gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA on pancreatic and brain tumor growth. The study identifies that gut dysbiosis leads to excessive development of Th17 cells and B cells that contribute to tumor growth. The study also demonstrates that microbial dependent IL-17 signaling increases DUOX2 signaling in tumor cells, which is relevant for accounting for its homeostatic host defense function during cancer therapy. The study highlights the complexities of IL-17-IL-17RA signaling in different compartments and its relevance for accounting for its homeostatic host defense function during cancer therapy.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they demonstrate the complexities of IL-17-IL-17RA signaling in different compartments and its relevance for accounting for its homeostatic host defense function during cancer therapy. The study identifies that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA leads to growth of pancreatic and brain tumors, which highlights the importance of addressing gut microbiome imbalances in cancer therapy. The study also suggests that targeted microbial ablation could be an effective strategy for blocking the compensatory loop and improving the efficacy of pharmacological inhibition of IL-17RA. Future research could explore the role of IL-17-IL-17RA signaling in other cancer types and the potential for targeting this pathway for cancer prevention and treatment.
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