Obesity-associated checkpoint blockade sensitivity is regulated by the diet-microbiota-immunity axis 4468

Abstract Description Globally, more people are overweight/obese than underweight, and obesity is associated with increased risk and mortality of several types of cancer. Paradoxically, obesity is associated with improved immune checkpoint inhibitor (ICI) efficacy in a variety of cancer types. While there is a body of literature demonstrating that the gut microbiome impacts ICI efficacy in preclinical models and human clinical trials, it is unknown how these observations relate to dietary habits and/or body weight. To investigate how diet influences cancer progression, we exposed our preclinical mouse model of lung cancer to 12 unique diets that lead to varying degrees of metabolic and immunological dysfunction over 15 weeks. We found that tumor growth and anti-PD-1 sensitivity are diet-dependent and vary significantly between obesity-promoting diets. Characterization of the gut microbiota by 16s rRNA uncovered bacterial families associated with ICI sensitivity that differed between obesity-inducing diets. To uncouple the effects of diet and adiposity, we showed that changing diet just 48 hours prior to the onset of treatment significantly alters ICI response independent of weight changes, which was also achieved with fecal microbiota transplants. These findings suggest that diet-induced changes to the gut microbiome may be driving differences in tumor growth and ICI sensitivity, and that diet and nutrition can be optimized to maximize the patient population that can benefit from ICI therapy. Funding Sources Canadian Cancer Society (707387) La Vie en Rose Canadian Institutes of Health Research (PJT-178306) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)