Exercise Boosts Cancer Immunotherapy Through Gut Microbes
Formate, a metabolite produced by gut bacteria, enhances cancer-killing immune cells.
Research reveals how exercise improves cancer treatment outcomes by changing the gut microbiome. A study illuminates that physical activity produces a compound called formate, which bolsters immunotherapy response in mice, potentially offering new strategies for human cancer treatment.
Breakthrough Discovery
A new study from the University of Pittsburgh demonstrates that exercise enhances the effectiveness of cancer immunotherapy by altering the gut microbiome in mice. The research identifies a specific compound, formate, produced by gut bacteria during exercise, as a key factor in improving cancer outcomes.
The findings, published in Cell, indicate that formate is associated with better outcomes in melanoma patients. The study highlights the potential of targeting the gut microbiome to enhance cancer treatment.
Experimental Design and Results
The lead author, Catherine Phelps, a student in Meisel’s lab, and her team compared mice that exercised regularly for four weeks with sedentary mice. The exercising mice exhibited smaller tumors and improved survival rates when challenged with an aggressive form of melanoma. However, these benefits diminished when the mice were germ-free or treated with antibiotics that depleted their gut microbiome.
The researchers further demonstrated that bacterial metabolites, rather than the bacteria themselves, drive these effects. Using a machine learning tool called SLIDE, they identified microbiota-derived formate as the key player.
Formate’s Impact on Immune Response
Further experiments revealed that formate enhances the potency of CD8 T cells, critical components of the immune system that kill cancer cells. In mouse models of melanoma, adenocarcinoma, and lymphoma, daily oral formate significantly inhibited tumor growth and improved survival rates. Formate also improved 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.”
Relevance to Human Health
To determine formate’s relevance in humans, Meisel and her team examined advanced melanoma patients undergoing immune checkpoint inhibitor therapy. Patients with high formate levels in their blood experienced better progression-free survival than those with low levels.
Fecal microbial transplants (FMT) from individuals with high formate levels into mice with aggressive melanoma resulted in enhanced T cell activity and better tumor control, suggesting a direct link between formate and improved immune response.
Implications for Future Therapies
Currently, FMT is under investigation as a potential therapy to improve immunotherapy outcomes in non-responders. However, the reasons why certain “super donor” stool samples lead to better outcomes remain unclear.
“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.”
The American Cancer Society estimates that there will be over 2 million new cancer cases in the US this year (American Cancer Society 2024), highlighting the urgent need for innovative treatment approaches.
Future Directions
Meisel and her team are now exploring whether exercise-induced changes in the gut microbiome may influence other diseases, such as autoimmune disorders. They also aim to understand the underlying mechanisms by which exercise affects the microbiome.
