Research led by scientists at NYU Grossman School of Medicine and Perlmutter Cancer Center has found that aerobic exercise can reprogram the immune system to reduce pancreatic tumor growth and amplify the effects of immunotherapy.

The study in mice and humans provides new insight into how the mammalian immune system, designed to attack foreign invaders like bacteria, can also recognize cancer cells as abnormal. The results suggest that exercise-induced increases in levels of the hormone adrenalin lead to changes in the immune system, including the activity of cells that respond to signaling protein interleukin-15 (IL-15), and that this can be harnessed therapeutically.

Dafna Bar-Sagi, PhD, senior vice president, vice dean for science, and CSO at NYU Langone Health, further explained, “Our work demonstrates that exercise, and related IL-15 signals, can prime treatment-resistant, pancreatic tumors for improved responses to immune-based therapeutics. That even mild exercise can profoundly alter the environment in tumors points to the potential of this approach in treating patients with a devastating disease burden and few options.”

As a result of the current work, the study team is collaborating with Perlmutter member Paul Oberstein, MD, director of gastrointestinal oncology at NYU Langone, as well as members from Rusk Rehabilitation, to launch a clinical trial assessing the immune effects of exercise in pancreatic cancer patients.

Bar-Sagi is senior author of the team’s published paper in Cancer Cell, which is titled “Exercise-induced engagement of the IL-15/IL-15Ra axis promotes anti-tumor immunity in pancreatic cancer.” In their paper, the team concluded: “These findings identify an exercise/immune modality that could be leveraged clinically for the treatment of pancreatic cancer.”

Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality, but as the authors noted, “little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited.” In fact, PDA is the third leading cancer cause of death in the United States, and there are currently no effective means to cure advanced disease.

The newly reported study found that exercise promoted the survival of CD8+ T cells sensitive to IL-15, and doubled the number of these cells homing in on pancreatic ductal adenocarcinoma tumors in mice. Such “effector” T cells have been shown by other studies to be capable of killing cancer cells. The team’s experiments in addition showed how aerobic exercise for 30 minutes five times a week reduced the rate of cancer formation by 50% in one mouse model of PDA, and reduced tumor weight by 25% in another model in which mice ran on treadmills for three weeks.

In collaboration with the University of Texas MD Anderson Cancer Center, the study authors then analyzed data from human patients who were enrolled in the “Preoperative Rehabilitation During Neoadjuvant Therapy for Pancreatic Cancer” clinical trial. Their data showed that patients who exercised before surgery to remove their pancreatic tumors had more CD8 effector T cells that expressed a protein called granzyme B, which confers tumor-cell killing ability. Also in that trial, which opened in 2017, those patients who exercised and had more of these cell types had 50% higher overall five-year survival than patients with fewer of them. “These results demonstrate that exercise training can induce increased CD8 T cell infiltration into human PDA tumors and potentially enhance their functional capacity,” the investigators stated. “… we observed a significant increase in the median overall survival of patients with high levels of intratumoral CD8 or GZMB in the exercise cohort, while no detectable difference associated with CD8 or GZMB status was seen in the control cohort.”

Over recent years, as the role of the IL-15 signaling in tumors has become clear, other researchers have attempted to treat cancer by direct infusion of the protein, but this, unfortunately, increased the risk of systemic inflammatory damage. Subsequent approaches have been designed to take into account that signaling proteins such as IL-15 fit into their receptor—IL-15Rα—on the surface of target T or natural killer (NK) cells, like a key into a lock. New drug candidates mimic these lock and key interactions, which transmit a message to activate the target cell.

Novartis has been developing a “super agonist” (S.A.) agent, NIZ985, which is designed to enhance IL-15/IL-15Rα pathway signals with reduced potential for harmful inflammatory effects, but this approach has not yet been tested in large numbers of pancreatic cancer patients, the authors pointed out. The work by Bar-Sagi and colleagues also showed that either aerobic exercise or treatment with NIZ985 increased the effectiveness of chemotherapy and an existing treatment that blocks the effect of a protein known as protein death receptor 1 (PD-1) in mice. To spare normal cells from immune attack, the immune system uses checkpoints—such PD-1—as sensors on immune cells that turn them off when they receive the right signal. Cancer cells hijack such checkpoints to inactivate immune responses.

Drugs that block the function of PD-1 can make tumors visible again to immune cells, but have had little efficacy against pancreatic ductal adenocarcinoma, which has a five-year survival rate of 10%. The newly reported studies found that PD-1 blockade increased the number of IL-15-responsive, cancer cell-killing CD8+ T cells in tumors of mice by 66% alone, but by 175% when combined with exercise.

The studies demonstrated that the combination of the IL-15 super agonist NIZ985 and PD-1-inhibiting therapy increased the survival of mice with advanced pancreatic cancer by 100%. “The immune-modulatory effects of exercise can be harnessed pharmacologically through the utilization of an IL-15 S.A.,” the team commented. “NIZ985 treatment prolongs mouse survival and enhances sensitivity to both ICB and standard-of-care chemotherapy.

“This study identifies a heretofore undescribed role for exercise in driving an immune-mediated anti-tumor effect in pancreatic cancer through the activation of the IL-15/IL-15Ra axis,” the investigators further stated. “In aggregate, these results identify the IL-15 S.A. + α-PD-1 combination as an effective strategy for eliciting a durable anti-tumor immune response.”

Emma Kurz, MD, PhD, a graduate student in the molecular oncology & tumor immunology PhD training program at NYU Grossman School of Medicine’s Vilcek Institute of Graduate Biomedical Sciences, added, “Our findings show, for the first time, how aerobic exercise affects the immune microenvironment within pancreatic tumors … The work helped to reveal that activation of IL-15 signaling in pancreatic cancer might be an important treatment approach in the future.”

Biological systems that fight disease and repair tissue are intertwined, the researchers suggest, with IL-15 signaling either encouraging the recovery of muscles after exercise or, as shown in the current work, amplifying immune attack on pancreatic cancer cells. “While future work will be required to determine the clinical feasibility of rigorous exercise regimens for patients with pancreatic cancer on a larger scale, our results validate the use of experimental models of exercise for the identification of new intervention strategies in a disease with few therapeutic options,” they concluded.