Exercise-Induced Engagement of the IL-15/IL15Rα axis Promotes Anti Tumor Immunity

The advent of immune checkpoint blockade has improved patient outcomes, providing durable disease control by reversing localized tumor-mediated immune-suppression and promoting anti-tumor immunity. Despite successes in melanoma and lung cancer, these therapies have largely failed in pancreatic ductal adenocarcinoma (PDA); a ‘cold’ tumor with the highest mortality rate among all major cancers. PDA is uniquely characterized by multiple intra-pancreatic tumor- and stroma-induced mechanisms of immune-suppression, and there remains a great need to explore creative approaches to improve anti-tumor immune responses in this disease. Herein, we show routine aerobic exercise provides tumor-protective benefits in murine PDA through modulation of both systemic and intra-tumoral immunity. Reversing immune-suppressive properties of both myeloid and T cell populations, we found the anti-tumor benefits of exercise require CD8 T cell activation and expansion in the tumor. Specifically, we report the sub-population of IL15Ra+ CD8 T cells is required for exercise-induced tumor protection and anti-tumor immunity, both of which are abrogated in the context IL-15 blockade. We further show that exercise-induced increases in intra-tumoral T cells are governed by adrenergic signaling and S1P-gradient dependent lymphocyte migration. Finally, we found that combination with aerobic exercise sensitizes pancreatic tumors to anti-PD-1 therapy. Overall, our work highlights the unique mechanisms governing exercise-induced tumor protection in PDA, and uncovers the importance of the interplay between systemic and intra-tumoral immunity to develop innovative strategies to reverse immune-suppression in this devastating disease. In this work, we set out to peform unibased analysis of the tumor immune microenvironment in pancretic cancer tumors in response to aerobic exercise. All live leukocytes in control and exercised tumors were isolated and were assessed for changes in the relative proportion of specific immune populations or changes to the transcriptional phenotype within each immune cell subset. Differences in the immune cell infiltrates of control and exercised mice would be used to inform mechanistic insights for exercise-induced tumor protection in pancreatic cancer.