Exercise-induced microbial folate metabolite enhances CD8 T cell antitumor immunity and promotes immunotherapy efficacy

Merkelcell.org Summary

Physical activity has been shown to potentially help the body fight cancer better and make certain treatments like immunotherapy work more effectively in cancers like melanoma, although the reason why is not clear.

To understand this, researchers at the University of Pittsburgh used mice with melanoma receiving immunotherapy and compared treatment outcomes between mice that exercised on a small treadmill versus those that did not. The mice that exercised responded better to immunotherapy, and the difference was linked to changes in their gut microbiome – a community of tiny, invisible organisms found in our intestines. Mice that exercised showed increased folate (also known as vitamin B9) processing, which is a series of essential biochemical reactions in our body that supports overall health. Excitingly, by studying the stool samples from humans, the researchers found that patients who responded best to immunotherapy had higher levels of a certain molecule that helps with folate processing.

This suggests that exercise might boost immunotherapy by modifying the gut ecosystem, along with the molecules it makes, for a better response. Although planned studies in humans are needed, this provides an encouraging direction to explore how simple lifestyle habits like exercise could potentially make immunotherapy more effective.

Abstract

Background: A sedentary lifestyle significantly increases the risk of cancer. In contrast, exercise has been associated with enhanced antitumor immunity and improved immune checkpoint inhibitor (ICI) efficacy in cancers like melanoma. However, the mechanisms through which exercise mediates antitumor effects remain obscure. Here, we show for the first time that exercise-induced changes to the microbiota are a key mechanism by which exercise promotes antitumor immunity via a previously undefined mechanism.

Methods: In this study, we use a mouse treadmill running model to define the mechanisms by which exercise enhances tumor immunity and ICI efficacy in a translationally relevant BRAFv600E melanoma tumor model which is ICI resistant.

Results: We first show that exercise-mediated tumor suppression relies upon adaptive immunity, specifically CD8 T cells, and an intact specific-pathogen-free microbiota in our model. Strikingly, we show that the compositionally distinct exercised microbiota is sufficient to confer tumor suppression, but must be metabolically active to do so, suggesting a key role for metabolites produced by the exercised microbiota. Accordingly, we find that exercise-microbiota produced metabolites are sufficient to restrain tumor growth in vivo and act directly on CD8 T cells to promote antitumor effector function in vitro. Through targeted and untargeted metabolomics approaches, we identify that exercise changes metabolic output of the microbiota by increasing bacterial folate (vitamin B9) metabolism. Accordingly, formate, a short-chain fatty acid and known intermediate of folate metabolism, is enriched in cecum contents and serum of exercised mice. Excitingly, we identify that the bacterial enzyme pyruvate formate lyase, required for bacterial formate synthesis, is significantly enriched in feces of immunotherapy responder patients across eight different study cohorts. In our model, we find that oral administration of formate alone is sufficient to restrain tumor growth, promote tumor antigen specific CD8 T cell effector function, and enhance immunotherapy efficacy in in a manner dependent on Nuclear Factor Erythroid 2-related factor 2 (Nrf2) signaling. Lastly, we demonstrate that Nrf2 signaling is required for the exercise-mediated antitumor effect in vivo.

Conclusions: Through this study, we have unveiled a previously unrecognized mechanism in which exercise, by modulating the production of a microbiota metabolite, improves ICI efficacy in melanoma. Our study will motivate a new line of investigations as it provides a rational mechanistic basis to design novel exercise, precision dietary, and microbial metabolite combinatorial therapeutic strategies to determine the clinical antitumor effect of microbial Nrf2 agonists, such as formate, in immunotherapy-resistant cancer patients.