Antitumor Immunity Is Induced by Exercise in Pancreatic Cancer

Systemic factors, including the role of aerobic exercise, have been gaining appreciation for their contribution to antitumor immune response. Previous work has associated aerobic exercise with reduced incidence and mortality in cancer, but little is known about its effects on pancreatic cancer. In a preclinical study, Kurz and colleagues showed that a low-intensity treadmill-running exercise regimen reduces murine pancreatic tumor growth due to an expansion of CD8⁺ T cells and a reduction in myeloid-derived suppressor cells. Exercise increased the number of tumor-infiltrating CD8⁺ T cells and enhanced activation and cytotoxicity markers, and CD8⁺ T-cell depletion blocked the exercise-induced reduction in tumor weight. Consistent with these findings, patients with pancreatic ductal adenocarcinoma who participated in exercise prior to surgical resection as part of a prospective clinical trial also had a higher number of infiltrating CD8⁺ T cells, and those within the exercise group who demonstrated high intratumoral CD8⁺ T cells had an increase in median overall survival. Mechanistically, activation of CD8⁺ T cells in exercised mice was induced by IL15, with IL15Rα⁺ CD8⁺ T cells being enhanced in these tumors. Furthermore, although immunotherapy is relatively ineffective in pancreatic cancer, combining exercise with anti–PD-1 therapy reduced tumor growth. Use of the IL15 superagonist NIZ985 was also found to decrease tumor growth and promote antitumor immunity in mouse models of pancreatic cancer, and dual treatment of mice with both the IL15 superagonist and anti–PD-1 therapy showed reduced tumor growth, prolonged survival, and expansion of immune cells. Similar results were also observed upon combination of the IL15 superagonist with standard-of-care chemotherapy and were further enhanced upon addition of anti–PD-1 therapy. Overall, the results of this study identified the role of exercise in promoting immune-mediated antitumor effects in pancreatic cancer and suggest that mimicking these effects with an IL15 superagonist could be an effective therapeutic strategy.

Kurz E, Hirsch CA, Dalton T, Shadaloey SA, Khodadadi-Jamayran A, Miller G, et al. Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer. Cancer Cell 2022;40:720–37.e5.

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