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.

Author Info: (1) Department of Cell Biology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA. (2) Department of Cell Biology, NYU Grossman School of Medicine, 550 1(s

Author Info: (1) Department of Cell Biology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA. (2) Department of Cell Biology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA. (3) Department of Pathology, Columbia University Irving Medical Center, 630 W 168th St., New York, NY 10032, USA. (4) Department of Cell Biology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA. (5) Applied Bioinformatics Laboratory, NYU Grossman School of Medicine, 227 East 30(th) St., New York, NY 10016, USA. (6) Department of Surgery, Trinity Health New England, 56 Franklin St., Waterbury, CT 06706, USA. (7) Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. (8) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. (9) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. (10) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. (11) Department of Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. (12) Department of Health Outcomes and Behavior, Moffit Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA. (13) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. (14) Department of Clinical Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. (15) Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA. (16) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; Gastrointestinal Medical Oncology and Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston TX, 77030, USA. (17) Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. (18) Permultter Cancer Center, NYU Langone Health, 160 East 34(th) St., New York, NY 10016, USA. (19) Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA. Electronic address: dafna.bar-sagi@nyulangone.org.