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

Cancer Cell. 2022 Jul 11;40(7):720-737.e5. doi: 10.1016/j.ccell.2022.05.006. Epub 2022 Jun 2.

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.

Trial registration: ClinicalTrials.gov NCT02295956.

Keywords: IL-15; PD-1; T cell; checkpoint blockade; exercise; immunology; immunotherapy; pancreatic cancer; super-agonist.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Pancreatic Ductal* / pathology
  • Cell Line, Tumor
  • Humans
  • Immunotherapy
  • Interleukin-15 / metabolism
  • Interleukin-15 / pharmacology
  • Interleukin-15 / therapeutic use
  • Pancreatic Neoplasms* / drug therapy
  • Receptors, Interleukin-15 / metabolism*
  • Tumor Microenvironment

Substances

  • Antineoplastic Agents
  • Interleukin-15
  • Receptors, Interleukin-15

Associated data

  • ClinicalTrials.gov/NCT02295956