Exercise slows tumor growth in pancreatic cancer

Aerobic exercise slows down pancreatic cancer growth in animal models and prolongs the survival of animals and patients with pancreatic cancer, according to the researchers.

“Our results show, for the first time, how aerobic exercise affects the immune microenvironment in pancreatic tumors,” noted lead author Emma Kurz, MD, PhD, of NYU Grossman School of Medicine, New York.

“The work revealed that the activation of IL-15 [interleukin-15] signaling in pancreatic cancer could be an important therapeutic approach in the future,” she added.

Work in mice also showed that exercise combined with drugs that inhibit programmed cell death (PD) increased the tumor growth-slowing effect.

The research was published online June 2 in cancer cell.

The researchers conducted a series of studies on mice with pancreatic cancer, all of which suggested that exercise slows tumor growth. The first set of mouse studies showed that the effects of exercise on tumor growth are dependent on CD8 T cells.

Given this finding, the team searched for data on patients with pancreatic cancer. They found this in a clinical trial in which patients with pancreatic ductal adenocarcinoma (PDA) prospectively underwent exercise prior to surgical resection.

“Consistent with our murine data, patients who participated in preoperative exercise showed significantly higher numbers of infiltrating CD8 T cells and a trend towards higher expression of granzyme B (GZMB) compared to matched historical controls. Additionally, we observed a significant increase in the median overall survival of patients with elevated intratumoral CD8 or GZMB levels in the exercise cohort, whereas no detectable difference associated with CD8 or GZMB status n was observed in the control cohort,” they report.

“These results demonstrate that exercise training can induce increased CD8 T cell infiltration in human PDA tumors and potentially improve their functional capacity,” comment the authors.

Sequential studies

The team investigated the mechanisms by which exercise leads to CD8 T cell activation in mice. The results showed that only IL-15 promotes the survival of CD8 T cells with a cytotoxic/effector phenotype, thus supporting a previously undescribed role for IL-15, as well as the IL-15 axis (IL- 15Rα), in promoting in-office antitumor immunity.

They then found that in mice, treatment with PD-1 drugs in combination with exercise more effectively reduced tumor growth compared to either approach alone – suggesting that exercise unlocks sensitivity. recalcitrant pancreatic tumors to anti-PD-1 treatment.

“Given our findings that the tumor protective properties of exercise are dependent on IL-15 signaling, we sought to characterize the effects of pharmacological activation of IL-15 in the PDA,” they wrote.

To demonstrate this, they used an IL-15 super-agonist (NIZ985) in mice with pancreatic cancer. The results showed a significant reduction in tumor growth and improved survival which, in turn, was associated with an increase in IL-15Rα as well as CD8 T cell counts.

They then assessed the effects of the combination of anti-PD-1 treatment and the super-agonist IL-15 in mice with pancreatic cancer. The results showed that this combination significantly slowed tumor growth and, above all, led to a pronounced prolongation of survival.

“These results identify IL-15 [super-agonist] plus an anti-PD-1 combination as an effective strategy to elicit a durable anti-tumor immune response,” the authors point out, adding that their findings “demonstrate that delineating the mechanisms of exercise-induced changes in the tumor immune milieu can lead to new approaches that improve the responsiveness of pancreatic tumors to immune and non-immune therapeutics. »

The authors did not disclose any relevant financial relationship.

Cancer cell. Published online June 2, 2022. Summary

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