Exercise-induced engagement of the IL-15/1L-15Rα axis promotes anti-tumor immunity in pancreatic cancer

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 IL15R alpha(+) 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-15R alpha 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 alpha PD-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.

Automated summary

Aerobic exercise reduces the growth of pancreatic ductal adenocarcinoma (PDA) by modulating the immune system. It promotes the accumulation of tumor-infiltrating immune cells and enhances the tumor-protective effects. In clinical samples, an increase of anti-tumor immune cells is observed. Targeting the IL-15/IL-15R alpha pathway shows promising results in treatment.