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

• DOI: 10.1016/j.ccell.2022.05.006
• Publication Date: 2022-06-02T14:42:14Z
• Authors: Emma Kurz; Carolina Alcantar...; Tanner Dalton; Sorin Alberto Sha...; Alireza Khodadadi...; George Miller; Sumedha Pareek; Hajar Rajaei; Chirayu Mohindroo; Seyda Baydogan; An Ngo-Huang; Nathan Parker; Matthew H.G. Katz; Maria Petzel; Emily Vucic; Florencia McAllister; Keri Schadler; Rafael Winograd; Dafna Bar-Sagi
• Keywords: Aerobic Exercise

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.