Gut microbes key to understanding how exercise boosts cancer immunity

A new study from the University of Pittsburgh shows for the first time how exercise improves cancer outcomes and enhances response to immunotherapy in mice by reshaping the gut microbiome.

The research, published in the journal Cell, found that these benefits are driven by a specific compound called formate, which is produced by gut bacteria in exercised mice and was also associated with better outcomes in patients with melanoma.

“We already knew that exercise increases the effectiveness of cancer immunotherapies, and we separately knew that exercise changes the microbiome in mice and humans,” said senior author Marlies Meisel, Ph.D., assistant professor in the Department of Immunology at the Pitt School of Medicine and affiliated with UPMC Hillman Cancer Center. “This study connects those dots by showing how exercise-induced changes in the gut microbiome boost the immune system and enhance immunotherapy efficiency via formate. These findings open the door to new therapeutic strategies targeting the microbiome.”

Lead author Catherine Phelps, a Graduate Program in Microbiology and Immunology student in Meisel’s lab, and the research team started by comparing mice that had completed four weeks of regular exercise to those that remained sedentary. The exercised animals had smaller tumors and better survival when challenged with an aggressive form of melanoma. But these benefits disappeared when they used germ-free rodents or treated the mice with antibiotics that killed off their gut microbiome.

“When we removed microbes from the equation, exercise no longer had any effect on cancer outcomes in mice,” said Phelps. “We were surprised to see such a clear signal that the beneficial effects of exercise were due to the microbiome.”

Next, the researchers showed that it was compounds, or metabolites, produced by bacteria rather than the bacteria themselves driving these effects.  They then used a machine learning tool called SLIDE that analyzes metabolic pathways to identify microbiota-derived formate as the key player.

Additional experiments showed that formate acts by enhancing the potency of CD8 T cells, the chief cancer-killing battalion of the immune system. In mouse models of melanoma, adenocarcinoma and lymphoma, daily oral formate greatly inhibited tumor growth and improved survival. Formate also enhanced the efficacy of immune checkpoint inhibitor immunotherapy in mice with melanoma.

“It’s really exciting to identify a specific bacterial metabolite that mimicked the effects of exercise in mice,” said Meisel. “In the future, formate could potentially be investigated as an adjuvant therapy to improve the efficacy of immune checkpoint inhibitors in non-responders.”

To investigate the relevance of formate in humans, Meisel and her team looked at advanced melanoma patients who received immune checkpoint inhibitor therapy. Those with high levels of formate in their blood had better progression-free survival than patients with low levels of the metabolite.

And when they performed fecal microbial transplants (FMT) from people with either high or low levels of formate into mice with aggressive melanoma, strikingly, the animals that received the high formate fecal transplant had enhanced T cell activity and better tumor control.

FMT is already being explored as a therapy to improve immunotherapy outcomes in non-responders. But why some “super donor” stool leads to better outcomes is not entirely clear.

“We want to describe metabolic biomarkers to identify FMT super donors because that’s really a black box,” said Meisel. “Currently everyone focuses on bacterial species, but our research suggests that it’s not just about which microbes are present, but what they are doing and which metabolites they are producing.”

Now, Meisel and her team are investigating whether exercise-induced changes to the gut microbiome could play a role in other diseases such as autoimmune disorders. They are also interested in understanding the mechanisms by which exercise influences the microbiome in the first place.

Other authors of the study are listed in the manuscript.

This research was supported by the National Institutes of Health (R01 DK130897, R01 CA293654, R21 CA259636, P50 CA254865, T32 CA082084, F32 CA284780, F31 CA290756, R01 HL160747, 1R01HL162658, T32 DK007665, AI118807, DK138912, AI188307, R01AI168478, R21AI163721, P30 CA047904, DP2 AI164325, S10OD023402, S10OD032141, R01CA253329 and U01CA272541), the Melanoma Research Alliance (820677), the Burroughs Wellcome Fund (1017880), the United States–Israel Binational Science Foundation (2021025), the University of Pittsburgh School of Medicine Department of Immunology, the University of Vienna Research Platform Active Ageing and the Interreg Slovakia–Austria program, the Kansas IDeA Network of Biomedical Research Excellence (P20 GM103418), and the Kansas State University Johnson Cancer Research Center Expansion and Innovation Award.

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