Exercise can improve the effectiveness of pancreatic cancer treatment

The immune attack of pancreatic cancer is enhanced by exercise.

According to recent studies, aerobic exercise reprograms the immune system to slow the development of pancreatic tumors and enhance the effect of immunotherapy.

A study that was recently published in the journal cancer cell, sheds new light on how the human immune system, designed to fight off foreign invaders such as bacteria, can also identify cancer cells as abnormal. According to the study authors, the increase in the hormone adrenaline caused by exercise alters the immune system, including the activity of cells that respond to the signaling protein interleukin-15 (IL-15).

According to the researchers, IL-15 signaling is involved in biological systems that prevent disease and repair tissue. Depending on the situation, this could aid muscle recovery after exercise or, in the case of this study, could enhance the immune system’s attack on pancreatic cancer cells.

The current study led by scientists New York University Grossman School of Medicine and Perlmutter Cancer Center found that exercise increases the number of surviving IL-15-sensitive CD8 T cells and doubles the number that are directed to pancreatic ductal adenocarcinoma (PDAC) tumors in mice.

Other studies have shown the ability of such “effector” T cells to destroy cancer cells. In other studies, mice used in a mouse model of PDAC that performed aerobic exercise for 30 minutes five times a week were shown to have a 50% lower rate of cancer development. Another study involving mice that ran on treadmills for three weeks showed a 25% reduction in tumor weight.

In collaboration with The University of Texas MD Anderson Cancer Center, the study authors found that patients enrolled in their “Preoperative Rehabilitation During Neoadjuvant Pancreatic Cancer” clinical trial – those who exercised before surgery to remove a pancreatic tumor had more effector CD8 T cells that expressed a protein called granzyme B, which provides the ability to kill tumor cells. Also, in this trial, which began in 2017, those patients who exercised and had more of these types of cells had a 50% higher five-year overall survival than patients with fewer of them.

“Our results show for the first time how aerobic exercise affects the immune microenvironment in pancreatic tumors,” says first author Emma Kurtz, MD, PhD, a postdoctoral fellow in the Department of Molecular Oncology and Tumor Immunology. Training program at the Wilczek Graduate Institute of Biomedical Sciences at NYU Grossman School of Medicine. “The work helped reveal that activation of IL-15 signaling in pancreatic cancer may be an important treatment method in the future.”

Enhancement of therapeutic response

In the past few years, as the role of IL-15 signaling in tumors has become clear, other researchers have attempted to treat cancer by direct administration of this protein, which unfortunately increases the risk of systemic inflammatory damage. Specialists have subsequently developed therapies based on the fact that signaling proteins such as IL-15 fit into receptor proteins (IL-15Rα), like a key in a lock, on the surface of target T or NK cells. New drug candidates mimic these lock-and-key interactions that transmit the message to target cell activation.

Pharmaceutical company Novartis is developing the “superagonist” NIZ985, which is designed to enhance IL-15/IL-15Rα pathway signaling with reduced potential for deleterious inflammatory effects. This approach has not yet been tested in large numbers of pancreatic cancer patients.

In the current study, Kurtz and his colleagues showed that either aerobic exercise or NIZ985 treatment increased the effectiveness of chemotherapy and an existing treatment that blocks the action of a protein called receptor death protein 1 (PD-1) in mice. To spare normal cells from immune attack, the immune system uses “checkpoints” such as PD-1 — sensors on immune cells that turn them off when they receive the right signal. Cancer cells hijack such checkpoints to deactivate immune responses.

Drugs that block PD-1 function can make tumors “visible” to immune cells again, but they are ineffective against pancreatic adenocarcinoma, which has a five-year survival rate of 10 percent. The PCC research team found that PD-1 blockade increased the number of IL-15-responsive, cancer-killing CD8+ T cells in mouse tumors by 66 percent alone, but by 175 percent when combined with exercise. In addition, the authors found that the combination of the IL-15 superagonist NIZ985 and PD-1-inhibitory therapy increased the survival of mice with advanced pancreatic cancer by 100%.

“Our work demonstrates that exercise and associated IL-15 signaling can promote treatment-resistant pancreatic tumors to improve response to immunotherapy,” says senior study author Daphne Bar-Sagi, Ph.D., senior vice president, Associate Dean for Science and Chief Scientist at NYU Langone Health. “That even mild exercise can significantly alter the environment in tumors indicates the potential of this approach in treating patients with devastating disease burden and multiple options.”

As a result of the current work, the research team is collaborating with Perlmutter Fellow Paul Oberstein, MD, director of gastrointestinal oncology at NYU Langone, as well as members of Rusk Rehabilitation, to begin a clinical trial evaluating the immune effects of exercise on the pancreas. cancer patients. In addition, the team plans to continue studying the potential effectiveness of the IL-15 superagonist in combination with chemotherapy to fight pancreatic tumors.

Reference: “Exercise-Induced Engagement of the IL-15/IL-15Rα Axis Promotes Antitumor Immunity in Pancreatic Cancer” Emma Kurtz, Carolina Alcantara Hirsch, Tanner Dalton, Sorin Alberto Shadalai, Alireza Haddadadi-Jamayran, George Miller, Sumedha Parekh, Hajjar Rajai, Chirayu Mohindro, Seyda Baidogan, An Ngo-Huang, Nathan Parker, Matthew H.G. Katz, Maria Petzel, Emily Vucic, Florence McAllister, Carrie Schadler, Raphael Winograd, and Daphne Bar-Sagi, 02 Jun 2022. Cancer cell.
DOI: 10.1016/j.ccell.2022.05.006

The study was funded by NIH/National Cancer Institute, NIH/National Center for the Advancement of Translational Sciences (NCATS), Cancer Research and Prevention Institute of Texas, Cancer Research and Prevention Institute of Texas, Canadian Institutes of Health Research and Perlmutter Cancer Center Grant Support.

The IL-15 superagonist (NIZ985) used in the study was provided by Novartis. None of the NYU Langone authors received financial compensation from Novartis. Research collaborations are governed by NYU Langone Health policies.