Gut Bacteria Metabolites Successfully Boost Immune Response to Melanoma Tumors

A new study from a team including University of Nebraska–Lincoln researchers is the first to show metabolites produced by certain bacteria in the gut can positively impact the body's immune response to cancer.

Published in Cell Reports Medicine and supported by Nebraska's Gnotobiotic Mouse Program, under direction of Amanda Ramer-Tait, the study helped pinpoint a specific gut bacterium that can boost the body's ability to fight melanoma.

Working with long-time collaborators at Cedars-Sinai and other institutions, Ramer-Tait co-led research showing that Bacteroides uniformis and the metabolites it produces can help suppress tumor growth. The bacterium converts the amino acid tryptophan into indoles, which boosted anti-tumor immunity in mice. The findings open the door to future microbiome- and diet-based strategies that could help more cancer patients respond to immunotherapy.

To determine whether the same mechanism might be relevant in people, researchers also analyzed samples from cancer patients receiving immunotherapy. Investigators found increased levels of enzymes used to produce indoles in those responding well to the therapy, suggesting the same phenomenon was contributing to patients' outcomes.

When I think about the role of the microbiome in cancer therapy, I see an opportunity to better understand why some patients respond well to treatments such as immune checkpoint inhibitors while others don't. Our study advances that idea by identifying a specific microbe and the metabolites it produces as one potential reason why patients respond differently to immunotherapies."

Ramer-Tait, Professor in Food Science and Technology, University of Nebraska–Lincoln

Through the Nebraska Gnotobiotic Mouse Program, the researchers were able to distinguish the important effects of tryptophan degradation. Only the indole-producing bacterial strain produced anti-tumor immunity. When a genetically modified Bacteroides uniformis that could no longer convert tryptophan into indoles was introduced to the germ-free mice, the anti-tumor effect disappeared, and tumors developed normally.

"Previous research established that gut bacteria affect the immune system and can help fight cancer," said Ze'ev Ronai, director of the Translational Research Institute at Cedars-Sinai and professor of surgery, who co-led the study with Ramer-Tait. "Our new findings are an important step forward because they give us a specific metabolite that can be used for future therapies."

The findings suggest that manipulating the gut microbiome - or providing beneficial bacterial metabolites directly - could someday help improve responses to cancer immunotherapy.

"Our idea is that down the road, we could design microbiome- or diet-based interventions that provide beneficial microbes or the dietary substrates they need to enhance a patient's response to immunotherapy," Ramer-Tait said. "What's especially exciting is that this approach has the potential to extend beyond melanoma because indoles play an important role in improving immune responses to other types of cancers as well."

In addition to Ramer-Tait and Ronai, study authors included Kristin Beede, research lab manager for Nebraska's Gnotobiotic Mouse Program. The work was supported by funding from the National Institutes to Health and the University of Nebraska Medical Center's Fred and Pamela Buffett Cancer Center.