Aerobic exercise slows pancreatic cancer growth in animal models and prolongs survival in both animals and patients with pancreatic cancer, say researchers.
“Our findings show, for the first time, how aerobic exercise affects the immune microenvironment within pancreatic tumors,” noted lead author Emma Kurz, MD, PhD, from at the NYU Grossman School of Medicine, New York.
“The work helped to reveal that activation of IL-15 [interleukin-15] signaling in pancreatic cancer might be an important treatment approach in the future,” she added.
The work in mice also showed that exercise combined with anti–programmed cell death (PD) inhibitor drugs increased the effect in slowing tumor growth.
The research was published online June 2 in Cancer Cell.
The investigators carried out a sequence of studies in 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.
In view of that finding, the team sought data on patients with pancreatic cancer. They found some in a clinical trial in which patients with pancreatic ductal adenocarcinoma (PDA) underwent exercise prior to surgical resection in a prospective manner.
“Consistent with our murine data, patients who participated in pre-operative exercise exhibited a significantly higher number of infiltrating CD8 T cells and a trend toward higher expression of granzyme B (GZMB) compared with matched historical controls. Furthermore, we observed a significant increase in the median overall survival of patients with high levels of intra-tumoral CD8 or GZMB in the exercise cohort, while no detectable difference associated with CD8 or GZMB status was seen in the control cohort,” they report.
“These results demonstrate that exercise training can induce increased CD8 T cell infiltration into human PDA tumors and potentially enhance their functional capacity,” the authors comment.
The team examined the mechanisms by which exercise leads to activation of CD8 T cells in mice. Results showed that only IL-15 promotes CD8 T-cell survival along 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 antitumor immunity in exercise.
They went on to discover that in mice, treatment with PD-1 drugs in combination with exercise more effectively reduced tumor growth compared with either approach alone — suggesting that exercise unlocks the sensitivity of 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 PDA,” they write.
To demonstrate this, they used an IL-15 super-agonist (NIZ985) in mice with pancreatic cancer. Results showed a significant reduction in tumor growth and an improvement in survival that in turn was associated with an increase in IL-15Rα as well as CD8 T-cell counts.
They then assessed the effects of combining anti-PD-1 therapy and the IL-15 super-agonist in mice with pancreatic cancer. The results showed that this combination significantly slowed tumor growth and, importantly, led to a pronounced prolongation of survival.
“These results identify the IL-15 [super-agonist] plus anti-PD-1 combination as an effective strategy for eliciting a durable anti-tumor immune response,” the authors emphasize, adding that their findings “demonstrate that delineation of the mechanisms of exercise-induced changes to the tumor-immune milieu can lead to new approaches that improve the responsiveness of pancreatic tumors to immune and non-immune based therapeutics.”
The authors have disclosed no relevant financial relationships.
Cancer Cell. Published online June 2, 2022. Abstract
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