Other How an unbalanced microbiome can kickstart tumour growth. Gut epithelial Interleukin-17 receptor A signaling can modulate distant tumors growth through microbial regulation (Dec 2023)

[Michael Harrop]

https://www.nature.com/articles/d42473-023-00412-1
https://www.cell.com/cancer-cell/abstract/S1535-6108(23)00434-8

The gut is a major source of IL-17. The various microorganisms that compose the gut microbiome routinely trigger the production of IL-17 by intestinal cells, and these signals in turn recruit immune cells to keep these microbial communities in check.

“Without normal intestinal IL-17 signalling, specific microbes can build up,” says McAllister. “And then the body, in an attempt to clear those bacteria, will generate even more IL-17-producing cells.” These cells in turn fuel untethered tumour growth, countering the effect of drugs designed to block IL-17 signalling. These effects extend well beyond the gut — the researchers showed that this microbially-induced boost in IL-17 production could stimulate aggressive tumour growth in the pancreas, as well as the brain.

McAllister is planning a future trial to test anti-IL-17 drugs in pancreatic cancer patients undergoing fecal microbiota transplantation, a treatment in which gut microbes from a healthy donor are administered to patients with dysfunctional, ‘unhealthy’ microbial communities. This could offer a safer clinical alternative to the approach described in the paper. “Antibiotics are good for proof of concept,” says McAllister. “But it would not be a long-term therapeutic option, given potential antibiotic resistance and many other detrimental effects.”

Highlights​

• Gut dysbiosis triggered by enteric IL-17RA deficiency induces remote tumor growth
• Inefficient gut IL-17 signaling triggers tumor promoting Th17 and B cells
• IL-17 inhibition with concurrent microbial depletion exerts anti-tumoral efficacy
• IL-17 expression is associated with DUOX2, primary target of IL-17, in human PDAC

Summary​

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.