Cancer Cell: Aerobic exercise can reprogram the immune system and enhance anti-tumor immunity

Pancreatic cancer is a malignant tumor of the digestive tract with a high degree of malignancy that is difficult to diagnose and treat, of which pancreatic ductal adenocarcinoma (PDAC) accounts for more than
95% of all pancreatic cancers.

In recent years, the incidence and mortality of pancreatic cancer have increased significantly, the early diagnosis rate of pancreatic cancer is not high, and it is often found at an advanced stage, at which time the cancer cells have spread, although some chemotherapy drugs are effective, but usually produce drug resistance, cancer immunotherapy is also difficult to play
.
Pancreatic cancer has a 5-year survival rate of less than 7%, making it the worst prognostic malignant tumor, so it is also known as the "king of cancers"
.
 

According to the latest WHO data, pancreatic cancer is the seventh cancer in China in 2020 (120,000 new cancer is expected to be added in 2020), and the sixth most deadly cancer (estimated death in 2020 is 120,000).

On June 2, 2022, a research team at NYU Grossman School of Medicine published a research paper
titled: Exercise-Induced Engagement of the IL-15/IL-15Rα axis Promotes Anti-Tumor Immunity in Pancreatic Cancer in Cancer Cell, a top international oncology journal.

The study found that aerobic exercise can reprogram the immune system, inhibit pancreatic cancer tumor growth and enhance anti-tumor immunity
.
The study also revealed the dependence of exercise-generated antitumor and immune activating effects on the IL-15 signaling pathway
.

The study demonstrated that pharmacological activation of IL-15 improves survival in mouse models and increases the sensitivity
of pancreatic tumors to immunotherapy and chemotherapy.
These findings identify an exercise/immune approach
to the treatment of pancreatic cancer with potential for clinical application.

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

In the latest study, the team used low-intensity treadmill running to simulate aerobic exercise, and a mouse model with slowly progressive pancreatic ductal adenocarcinoma (PDAC) was subjected to 30 minutes of low-intensity running five times a week
.
The results showed that this exercise effectively alleviated tumorigenesis and reduced the tumor formation rate by 50%.

In another group of mouse models, mice that started exercising 12 days after transplanting the tumor resulted in a 25 percent
reduction in tumor weight.
These findings suggest that aerobic exercise exerts antitumor effects
in both the initial stage of tumor and the progression of pancreatic ductal adenocarcinoma.

Next, the research team, in collaboration with researchers at MD Anderson Cancer Center, validated it in human pancreatic cancer patients, and they found that those who exercised before undergoing pancreatic cancer removal surgery had a greater number of CD8 effector T cells that expressed a protein called granzyme B (GZMB) that gives them the ability to
kill tumor cells.
Another clinical trial, which began in 2017, showed that patients who exercised and had more CD8 effector T cells had a 50 percent better 50-year
survival rate.

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

Over the past few years, as the role of IL-15 signaling in tumors has become clearer, researchers have tried to treat cancer with direct infusion of IL-15, but unfortunately, this has increased the risk of
systemic inflammatory damage.
After that, some studies began to focus on IL-15 receptor protein - IL-15Rα
, which is located on the surface of T cells and NK cells.
The relationship between IL-15 and IL-15Rα is like a key and a lock
.
There are new drug candidates that mimic these "key-to-what" interactions, transmitting information to activate target cells
.

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

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

The emergence of immune checkpoint inhibitors has changed the cancer treatment landscape, but it has little effect
on pancreatic ductal adenocarcinoma.
In this study, they found that anti-PD-1 monoclonal antibody treatment alone increased the number of IL-15-sensitive, tumor-killing CD8+ T cells in mouse pancreatic tumors by 66%.

And when combined with exercise, it increases by 175%.

In addition, the research team also found that the combination of NIZ985, a super-agonist of IL-15, with anti-PD-1 monoclonal antibody, was able to improve the survival rate of advanced pancreatic cancer mice by 100%.

Dafna Bar-Sagi, who led the study, said the study showed that exercise and associated IL-15 signaling can improve the response
of drug-resistant pancreatic cancer to immunotherapy.
Even low-intensity exercise can profoundly alter the tumor microenvironment, illustrating the potential
of exercise in the treatment of a deadly tumor such as pancreatic cancer.

Based on the results of this study, the research team is collaborating on a human clinical trial to evaluate the immune effects
of exercise on pancreatic cancer patients.
In addition, the research team plans to continue to explore the effects
of IL-15 superagonists in combination with chemotherapy drugs in the treatment of pancreatic cancer.

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