Aerobic exercise 5 times a week for 30 minutes each time can reduce the risk of cancer by 50%

In a new study, researchers from NYU Grossman School of Medicine and the University of Texas MD Anderson Cancer Center found that aerobic exercise can reprogram the immune system to reduce pancreatic tumor growth and amplify the effects of immunotherapy. The relevant research results were published online in the journal Cancer Cell on June 2, 2022, with the title "Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer".

The new study provides new insights into how the immune system in mammals, which is designed to attack foreign invaders such as bacteria, can also recognize cancer cells as abnormal. The authors show that the increase in adrenaline levels caused by exercise led to changes in the immune system, including the activity of cells that respond to the signaling protein interleukin-15 (IL-15).

The authors say biological systems that fight disease and repair tissue are intertwined with IL-15 signaling, which, depending on the context, can either encourage muscle recovery after exercise or amplify immune attacks on pancreatic cancer cells.

The new study found that exercise promoted the survival of IL-15-sensitive CD8 T cells and doubled their homing to pancreatic ductal adenocarcinoma (PDAC) tumors in mice. Such "effector" T cells have been shown by other studies to kill cancer cells. Other tests found that 30 minutes of aerobic exercise five times a week reduced cancer formation by 50% in one PDAC mouse model, while three weeks of treadmill running reduced tumor weight by 25% in another mouse model.

The authors then found that in human patients enrolled in the Preoperative Rehabilitation During Neoadjuvant Therapy for Pancreatic Cancer clinical trial, those who exercised before having pancreatic tumors surgically removed had more CD8 effector T cells that express a protein called granzyme B, which confers tumor cell-killing abilities. Furthermore, in the trial, which began in 2017, patients who exercised and had more of these cell types had a 50% higher overall survival rate over a five-year period than those with fewer of these cells.

"Our results are the first to show how aerobic exercise affects the immune microenvironment within pancreatic tumors," says Emma Kurz, PhD, first author of the paper from NYU Grossman School of Medicine. "This new research helps reveal how activation of IL-15 signaling in pancreatic cancer could be an important therapeutic approach in the future."

Improve treatment response

Over the past few years, as the role of IL-15 signaling in tumors became clear, other scientists have tried to treat cancer by directly infusing the protein, which unfortunately increases the risk of systemic inflammatory damage. Subsequently, the field has designed treatments based on the fact that signaling proteins such as IL-15 fit into receptor proteins (IL-15Rα) on the surface of target T cells or NK cells, just like a key fits into a lock. New drug candidates mimic these "lock-key" interactions to deliver information to activate target cells.

Novartis Pharmaceuticals has been developing a “superagonist” agent, NIZ985, which is designed to enhance IL-15/IL-15Rα pathway signaling while reducing the potential for harmful inflammatory effects. This approach has not yet been tested in a large number of pancreatic cancer patients.

In the new study, Kurz and colleagues found that both aerobic exercise and treatment with NIZ985 boosted the effectiveness of chemotherapy and an existing drug that blocks the PD-1 receptor in mice. To protect normal cells from immune attack, the immune system uses "immune checkpoints" on the surface of immune cells, such as PD-1, that shut them down when they receive the right signals. Cancer cells hijack these immune checkpoints, disabling the immune response.

Image from Cancer Cell, 2022, doi:10.1016/j.ccell.2022.05.006.

Drugs that block PD-1 function can make tumors "visible" to immune cells again, but have little effect on pancreatic ductal adenocarcinoma, which has a five-year survival rate of 10%. The authors found that PD-1 blockade increased the number of IL-15-responsive, cancer-killing CD8+ T cells in mouse tumors by 66% alone, but by 175% when combined with exercise. In addition, they found that the combination of the IL-15 superagonist NIZ985 and PD-1 inhibition therapy increased the survival of mice with advanced pancreatic cancer by 100%.

"Our study demonstrates that exercise and associated IL-15 signaling can make treatment-resistant pancreatic tumors more responsive to immune-based therapies," says senior author Dafna Bar-Sagi, MD, PhD, senior vice dean for the NYU Grossman School of Medicine. "Even mild exercise can profoundly alter the tumor environment, suggesting that this approach has potential in treating patients with a devastating disease burden and few treatment options."

As a result of the new study, the authors are working with Paul Oberstein, MD, chief of gastrointestinal oncology at NYU Grossman School of Medicine, and members of the Riske Institute for Rehabilitation Medicine to initiate a clinical trial designed to evaluate the immune effects of exercise on pancreatic cancer patients. In addition, the team plans to continue exploring the potential efficacy of combining IL-15 superagonists with chemotherapy against pancreatic tumors.

References:

Emma Kurz et al. Exercise-Induced Engagement of the IL-15/IL-15Rα axis Promotes Anti-Tumor Immunity in Pancreatic Cancer. Cancer Cell, 2022, doi:10.1016/j.ccell.2022.05.006.