When normal gut microbiota is disrupted, whether it's from infections, diet or medication, the imbalance can lead to wider systemic manifestations, such as enhanced tumour growth.Credit: nopparit/Getty Images
Promising therapeutic strategies for shutting down tumour growth can fail in unexpected ways. Consider interleukin-17 (IL-17), an immune signalling factor that balances the gut microbiome, but also stimulates cancer onset and progression in the pancreas and other organs. However, drugs that act on this pathway have demonstrated limited benefit for slowing tumour growth.
A team led by The University of Texas MD Anderson Cancer Center oncologist, Florencia McAllister, has now traced the roots of this problem to the communities of bacteria that live within the intestine, and which play a critical role in modulating the immune function of their hosts (Chandra, V. et al. Cancer Cell 42, 85-100; 2024).
Gut feeling
McAllister was initially interested in pursuing a clinical trial to test drugs that inhibit IL-17 signalling as cancer therapeutics. This effort was derailed by unsettling results from experiments in which her team implanted tumours in recipient animals with deletion of the gene encoding the primary receptor for IL-17. “Instead of becoming smaller, the tumours became larger,” says McAllister. “And we didn’t understand why.”
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. McAllister and colleagues conducted experiments in which they exclusively deleted the IL-17 receptor in intestinal cells, leaving expression intact elsewhere in the body and again observed larger tumours. These results confirmed that host-microbe interactions in the gut were responsible for this rise in IL-17 production, and revealed that disruption of IL-17 receptor-mediated signalling was setting a damaging feedback loop into motion.
“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.
Breaking the cycle
The good news is that McAllister’s team has managed to break this destructive loop by administering antibiotics to rodents with deficient IL-17 signaling. “When you ablate the excess of microbes, the effect is gone,” she says. If this physiological mechanism is validated in humans, it could guide development of treatment regimens in which IL-17 inhibition is coupled with other drugs that keep the gut microbiome in check. This could also be an important strategy for people with autoimmune disorders like psoriasis, which are often treated with IL-17-targeting drugs.
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.”