Role of physical exercise-induced microbiota changes in immunotherapy resistant preclinical melanoma

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT: Physical inactivity is a leading risk factor for development of non-communicable diseases, including cancers. Increased exercise has been shown to benefit cancer patients by improving response to immune checkpoint inhibitor (ICI) treatments. Preclinical models suggest exercise facilitates these benefits by modulating antitumor immune responses, including changes to CD8 T cell tumor infiltration and effector function. However, mechanisms by which exercise induces these immunologic changes remain poorly understood. Exercise is known to change the composition and function of the gut microbiota. Many researchers, including our lab, have demonstrated that gut microbiota composition dictates efficacy of ICI therapy in melanoma. Thus, in our work, we seek to uncover whether and if so how exercise-induced changes to the microbiota impact on tumor immunity and ICI efficacy, a concept which has never been tested before. In key preliminary data we show that treadmill running exercise restrains YUMM1.7 melanoma tumor growth, prolongs survival, and sensitizes this ICI-resistant model to αPD-1 therapy. Exercise-driven tumor suppression requires adaptive immunity, specifically CD8 T cells, and exercise promotes enhanced antitumor effector cytokine production in CD8 T cells (including interferon- gamma producing Tc1 cells). Excitingly, we find that our exercise regimen induces compositional changes to the gut microbiota, and that the microbiota is required for exercise tumor suppression. We further show that fecal microbiota transplantation (FMT) of the exercised microbiota (ex-microbiota) is sufficient to enhance systemic Tc1 immunity and confer tumor suppression in sedentary mice; but only when the ex-microbiota is metabolically active, suggesting that microbial metabolites produced by the ex-microbiota play a key role. Preliminary tumor homogenate cultures indicate an expansion of three bacterial species within tumors of exercised mice, begging the question whether exercise-induced compositional changes to the tumor microbiota contribute to immunomodulatory effects of exercise. Our central hypothesis is that physical exercise induced microbiota changes promote anticancer Tc1 cell immunity and therefore sensitize ICI-resistant melanoma to ICI therapy. In this proposal, we will assess if and how ex microbiota metabolites (i) act directly upon CD8 T cells to promote antitumor function, (ii) improve tumor antigen specific CD8 T cell immunity, and (iii) improve sensitivity to ICI therapy (Aim 1). Further, we will evaluate the requirement and sufficiency of the intratumoral microbiome for exercise-mediated tumor suppression and ICI sensitization in our model (Aim 2). Successful completion of this study will identify novel mechanisms by which the exercised-microbiota impacts on CD8 T cell immunity and elucidate microbial therapeutic targets that can be used to reproduce key immunomodulatory benefits of exercise for cancer patients.