Grant: Project Grant

Immune checkpoint inhibitors (ICI) have transformed cancer treatment by enabling the immune system to better recognize and attack tumours. However, these treatments benefit only a minority of patients. Surprisingly, people with a higher body mass index (BMI) often respond better to ICI, even though obesity is a well-known risk factor for developing cancer. The reason for this paradox has remained unclear. Our recent research suggests that the benefit is not caused by obesity itself, but by the types of foods people eat that can lead to obesity (known as "obesogenic diets"). In mouse models of lung cancer, we found that obesogenic diets quickly reshape the gut microbiome (i.e. bacteria that live in our digestive system) in ways that enhance ICI effectiveness, even before any weight gain occurs. In particular, we identified a beneficial gut bacterium that responds to certain types of dietary fats by producing a metabolite that primes the immune system. This metabolite boosts the number and activity of cytotoxic T cells, a type of immune cell essential for the success of ICI. In this project, we will uncover exactly how diet, gut microbes, and metabolites work together to influence cytotoxic T cell function and cancer immunotherapy outcomes. We will determine how specific nutrients in food alter microbial metabolism, how the resulting metabolites signal to immune cells, and whether these pathways are active in cancer patients receiving ICI. Our ultimate goal is to develop simple, short-term dietary strategies (such as adjusting fat sources or adding certain foods) that can "tune" the gut microbiome to improve immunotherapy. This understanding will provide a foundation for developing safe, low-cost, and widely accessible strategies to enhance patient responses to cancer treatment.