Kurz et al. demonstrated that aerobic exercise enhances antitumor immunity in murine models and human pancreatic ductal adenocarcinoma (PDA). In an orthotopic PDA tumor model, exercise reduced myeloid-derived suppressor cells, promoted CD8+ T cell infiltration and activation, and reduced tumor growth in CD8+ T cell-dependent manner. Exercise-mediated antitumor and immune activating effects were dependent on IL-15 signaling, and IL-15 superagonist (NIZ985) reduced tumor growth, prolonged survival, increased sensitivity to immunotherapy and chemotherapy, and promoted durable immune response in the PDA tumor model.
Contributed by Shishir Pant
ABSTRACT: Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality. However, little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited. Herein, we show that aerobic exercise reduces PDA tumor growth, by modulating systemic and intra-tumoral immunity. Mechanistically, exercise promotes immune mobilization and accumulation of tumor-infiltrating IL15Rα+ CD8 T cells, which are responsible for the tumor-protective effects. In clinical samples, an exercise-dependent increase of intra-tumoral CD8 T cells is also observed. Underscoring the translational potential of the interleukin (IL)-15/IL-15Rα axis, IL-15 super-agonist (NIZ985) treatment attenuates tumor growth, prolongs survival, and enhances sensitivity to chemotherapy. Finally, exercise or NIZ985 both sensitize pancreatic tumors to αPD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.