Pancreatic cancer is notoriously deadly, with 89 percent of patients dying within five years of their diagnosis. Treatment is difficult; the tumor’s microenvironment suppresses the immune response, and oftentimes the disease goes undetected until it has reached an advanced stage. However, exercise seems to help those who are able to get up and walk around, experts tell The Scientist, and new research seems to have uncovered why. The study reinforces the notion that exercise, when feasible, might be a worthwhile component of cancer patients’ care.
In a Cancer Cell paper published June 2, researchers report that mice with pancreatic ductal adenocarcinoma that exercised regularly survived for longer and were healthier than those that did not, thanks to both an enhanced antitumor immune response and increased sensitivity to chemotherapy. While the link between exercise and improved disease outcomes has been demonstrated in human pancreatic cancer patients, the new study is the first to reveal a biological mechanism responsible, says Emma Kurz, a graduate student of molecular oncology and tumor immunology at NYU Grossman School of Medicine and first author on the paper.
“It’s really hard to get an animal with this type of pancreatic cancer to respond to any immunotherapy,” Kurz adds. Doing so “in a pretty meaningful way that actually improves their survival was a big moment for me as a researcher in this field.”
Study coauthor and cancer biologist Dafna Bar-Sagi of NYU Grossman adds that “this is something that doesn’t happen a whole lot, for this disease, even in experimental models.”
Mitigating pancreatic cancer with exercise
In the study, mice were broken into two groups. One group performed aerobic exercise on a miniature treadmill for half an hour at a time, five to seven days a week for six weeks. The mice were supervised to ensure each got about the same amount of exercise—Kurz compares the speed to a fast walk or a slow jog in people. The other group didn’t exercise but were still placed on the treadmill when it was powered off. Three weeks after completing the regimen, the mice who exercised had smaller tumors had fewer immunosuppressive myeloid cells in the tumor microenvironment, and responded better to pharmaceutical treatments.
The experiment involved supervising five mice at a time as they ran on a tiny treadmill for 30 minutes per day.
COURTESY OF EMMA KURZ; THE BAR-SAGI LAB AT NYU LANGONE SCHOOL OF MEDICINE
Specifically, the researchers found that aerobic exercise activated interleukin-15 (IL-15), a cytokine typically released by muscles during exercise, which triggers inflammation to fight pathogens. That activation mobilized a subset of CD8 T cells—immune cells that target and kill cancer cells—that carried an IL-15 receptor, ultimately allowing them to better infiltrate and engage with the tumor. The mice that exercised were found to have more of these CD8 T cells in and around their tumors.
“The study by Kurz et. al. is an important one considering pancreatic cancer has a uniformly poor prognosis and is predicted to become the second leading cause of cancer death in the United States by 2025,” Roopali Roy, a Boston Children’s Hospital and Harvard Medical School surgeon and cancer researcher who didn’t work on the study, tells The Scientist over email. She adds that pancreatic tumors are particularly resistant to immunotherapies that have shown some success in lung, breast, and skin cancers.
“There is an ongoing effort in this field to reprogram the pancreatic tumor microenvironment to improve T-cell infiltration of the tumor such that immunotherapy treatments would have a better chance of success,” Roy writes. “The authors in the current study show that moderate exercise can increase the number of infiltrating CD8 T cells in tumors and reduce the numbers of [myeloid-derived suppressor cells] which have an immunosuppressive function.”
IL-15 drugs versus exercise
The researchers took their experiment a step further to test whether IL-15 or some other aspect of exercise improved disease outcomes. To do so, they treated mice that didn’t exercise with a superagonist that ramped up the activity of the IL-15 receptor—and observed the same health benefits as in the active mice. When superagonist treatment was combined with chemotherapy and PD-1 immunotherapy, Kurz explains, the mice improved even further. On the other hand, she adds, depleting IL-15 signaling erased the effect of exercise altogether.
“For me, the nice thing about this paper is this linkage—they showed a nice linkage between the exercise and the infiltration of CD8 T cells,” says Hanne Ostergaard, who studies CD8 T cells at the University of Alberta and didn’t work on the study. She particularly applauds the study’s authors for illustrating a mechanistic link between exercise or superagonist treatment and outcomes “in a very hard-to-treat cancer.” That link, she says, had been established for some cancers but was lacking in the pancreatic tumor literature.
Bar-Sagi tells The Scientist that “it’s true, strictly speaking” that superagonist treatment was able to substitute for exercise, which she thinks is good news because many pancreatic cancer patients are too sick for physical activity. However, she notes that “there are obviously other beneficial effects of exercise that could potentially be additive to what is just pharmacological intervention.”
Thanks to frozen human tissue samples provided by study coauthors from the MD Anderson Cancer Center, the researchers were able to do preliminary tests of their animal study findings in humans as well. The samples taken from human pancreatic cancer patients who participated in an exercise program prior to surgery contained a significantly higher number of CD8 T cells that better infiltrated their tumors compared with non-exercising controls, according to the study.
“The exciting thing to me was that they had a mechanism going from exercise to outcomes in the mouse model but that they also saw this increase in humans,” Ostergaard says. However, she adds that differences between human and mouse tumor microenvironments necessitate further human study before any definitive clinical conclusions can be drawn. Roopali also notes that the mice in the experiment were young—just eight weeks old—and might not offer the best comparison to pancreatic cancer patients, who tend to be middle-aged or older.
Bar-Sagi and Kurz explain that they’ve already been granted approval to proceed with a clinical trial in which patients will undergo partially supervised exercise—reducing the risk of errors from self-reporting data—just like the mice did. The trial, Kurz explains, will be the first to look at the immunological readouts after exercise in pancreatic cancer, and the authors plan to launch a subsequent trial testing the effects of the IL-15 superagonist. Both coauthors express cautious optimism about the prospect of improving treatments for the particularly difficult cancer.
“That’s really the part that is critically important,” Bar-Sagi says, “because we find now a modality, exercise or some form of intervention, that seems like it could work; it has a mechanism. It’s not that we just find in the mouse that the tumors are regressing, but there is a really good foundation for something that might work.”