Aerobic exercise reprograms the immune system and enhances anti-tumor immunity

Pancreatic cancer (PC) is a highly malignant digestive tract tumor that is difficult to diagnose and treat, with pancreatic ductal adenocarcinoma (PDAC) accounting for more than 95% of all pancreatic cancers.

The incidence and mortality rate of pancreatic cancer have both increased significantly in recent years. The early diagnosis rate of pancreatic cancer is low, and when it is detected, it is often at an advanced stage, when cancer cells have already spread. Pancreatic cancer has a 5-year survival rate of less than 7% and is the worst malignant tumor in terms of prognosis, earning it the moniker "king of cancers".

On June 2, 2022, a team of New York University Grossman School of Medicine researchers published a study in Cancer Cell, a leading international oncology journal, titled "Exercise-Induced Engagement of the IL-15/IL-15R Axis Promotes Anti-Tumor Immunity in Pancreatic Cancer". Aerobic exercise reprogrammed the immune system to inhibit pancreatic cancer tumor growth and boost anti-tumor immunity, according to this study, which also revealed that the anti-tumor and immune activating effects of exercise are dependent on the IL-15 signaling pathway.

Exercise promotes the survival of IL-15-sensitive CD8 T cells and doubles their homing to pancreatic ductal adenocarcinoma (PDAC) tumors in mice, and the resulting effector T cells have been shown to kill cancer cells in other studies.

The team used low-intensity treadmill running to simulate aerobic exercise in this latest study, subjecting a mouse model with slowly progressive pancreatic ductal adenocarcinoma (PDAC) to 30 minutes of low-intensity running five times a week. The results demonstrated that this exercise effectively reduced tumorigenesis, with a 50% decrease in tumor formation. Another group of mouse models began exercising 12 days after tumor transplantation, resulting in a 25% reduction in tumor weight. These findings imply that aerobic exercise has an anti-tumor effect during both the tumor initiation and progression stages of pancreatic ductal adenocarcinoma.

The team then collaborated with MD Anderson Cancer Center researchers to validate this in human pancreatic cancer patients, discovering that those who exercised prior to pancreatic cancer resection had higher numbers of CD8-effector T cells, which express a protein called granzyme B (GZMB) that confers the ability to kill tumor cells. Another clinical trial, which began in 2017, found that patients who exercised and had a higher number of CD8-effector T cells had a 50% higher 5-year survival rate.

Emma Kurz, first author of the paper, said the study is the first to show how aerobic exercise affects the immune microenvironment within pancreatic tumors. This study helps reveal that activation of IL-15 signaling in pancreatic cancer may be an important treatment in the future.

Pharmaceutical giant Novartis has been developing a "super agonist" drug, NIZ985, designed to enhance IL-15/IL-15Rα pathway signaling and reduce the potential for harmful inflammatory effects. However, this approach has not been tested in large numbers of pancreatic cancer patients.

In this study, they found that both aerobic exercise and treatment with NIZ985, a "super agonist" drug developed by Novartis, improved the effectiveness of chemotherapy and immune checkpoint inhibitor (anti-PD-1 monoclonal antibody) therapy.

The advent of immune checkpoint inhibitors has changed the landscape of cancer treatment, but has had little effect on pancreatic ductal adenocarcinoma. In this study, they found that treatment with anti-PD-1 monoclonal antibody alone increased the number of IL-15-sensitive, tumor-killing CD8+ T cells in mouse pancreatic tumors by 66%. And when combined with exercise, there was a 175% increase. In addition, the team found that the combination of NIZ985, a super agonist of IL-15, with anti-PD-1 monoclonal antibody was able to increase the survival rate of mice with advanced pancreatic cancer by 100%.

The study's leader, Dafna Bar-Sagi, stated that the findings show that exercise and associated IL-15 signaling can improve the response of drug-resistant pancreatic cancer to immunotherapy. Even low-intensity exercise can significantly alter the tumor microenvironment, demonstrating the potential of exercise in the treatment of a deadly tumor like pancreatic cancer.

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