PAnchor cancer is notoriously deadly, with 89% of patients dying within five years of their diagnosis. Treatment is difficult; the tumor microenvironment suppresses the immune response and often the disease goes undetected until it has reached an advanced stage. However, exercise appears to help those who are able to stand and walk, experts say The scientist, and new research appears to have uncovered why. The study reinforces the idea that exercise, when possible, could be a helpful part of caring for cancer patients.
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In a cancer cell article published on June 2, researchers report that mice with pancreatic ductal adenocarcinoma who exercised regularly survived longer and were healthier than those who did not, thanks to both an immune response improved antitumor and increased sensitivity to chemotherapy. While the link between exercise and improved disease outcomes has been shown in human pancreatic cancer patients, the new study is the first to reveal a biological mechanism responsible, says student Emma Kurz graduated in Molecular Oncology and Tumor Immunology at NYU Grossman School of Medicine. and first author on paper.
“It’s really difficult to get an animal with this type of pancreatic cancer to respond to immunotherapy,” Kurz adds. Doing it “in a pretty significant way that actually improves their survival was a big moment for me as a researcher in this field.”
Study co-author and NYU Grossman cancer biologist Dafna Bar-Sagi adds that “this is something that doesn’t happen a lot, for this disease, even in experimental models.”
Mitigating pancreatic cancer with exercise
In the study, the mice were divided 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 that each got about the same amount of exercise – Kurz likens the speed to a brisk walk or a slow jog in people. The other group did not exercise but were still placed on the treadmill when it was turned off. Three weeks after completing the diet, the mice that exercised had smaller tumors, had fewer immunosuppressive myeloid cells in the tumor microenvironment, and responded better to pharmaceutical treatments.
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The experiment involved supervising five mice at a time as they ran on a tiny treadmill for 30 minutes a day.
COURTESY OF EMMA KURZ; THE BAR-SAGI LABORATORY OF THE 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 off pathogens. This 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. 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 significant given that pancreatic cancer has a uniformly poor prognosis and is expected to become the second leading cause of cancer death in the United States by 2025,” said Roopali Roy, surgeon and cancer researcher at Boston Children’s Hospital and Harvard Medical School. t work on the study, tells The scientist by email. She adds that pancreatic tumors are particularly resistant to immunotherapies which have shown some success in lung, breast and skin cancers.
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“There is an ongoing effort in this field to reprogram the pancreatic tumor microenvironment to improve T-cell infiltration into the tumor so that immunotherapy treatments have a better chance of success,” Roy writes. “The authors of the current study show that moderate exercise can increase the number of infiltrating CD8 T cells in tumors and reduce the number of [myeloid-derived suppressor cells] which have an immunosuppressive function.
IL-15 drugs versus exercise
The researchers took their experiment one step further to test whether IL-15 or another aspect of exercise improved disease outcomes. To do this, they treated non-exercising mice with a superagonist that increased IL-15 receptor activity and observed the same health benefits as in the active mice. When superagonist treatment was combined with chemotherapy and PD-1 immunotherapy, Kurz says, the mice got even better. On the other hand, she adds, depletion of IL-15 signaling completely erased the effect of exercise.
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“For me, the good thing about this paper is this link – they showed a good link between exercise and CD8 T cell infiltration,” says Hanne Ostergaard, who studies CD8 T cells at the University of Alberta and did not work on the study. She particularly applauds the study authors for illustrating a mechanistic link between exercise or superagonist therapy and outcomes “in a very difficult to treat cancer.” This link, she said, had been established for some cancers but was missing in the pancreatic tumor literature.
Bar-Sagi tells The scientist that “it’s true, strictly speaking” that the superagonist treatment was able to replace exercise, which she thinks is good news because many pancreatic cancer patients are too sick to do any physical activity. However, she notes that “there are obviously other beneficial effects of exercise that could potentially add to what is only a pharmacological intervention.”
Using frozen human tissue samples provided by study co-authors at the MD Anderson Cancer Center, the researchers were also able to perform preliminary testing of the results of their animal studies in humans. According to the study, samples taken from human pancreatic cancer patients who participated in an exercise program before surgery contained significantly higher numbers of CD8 T cells that better infiltrated their tumors compared to controls. without exercise.
“What interested me was that they had a mechanism from exercise to outcome in the mouse model, but they also saw this increase in humans,” Ostergaard says. However, she adds that the differences between human and mouse tumor microenvironments require further study in humans before firm 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 with pancreatic cancer patients, who tend to be middle-aged or older.
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Bar-Sagi and Kurz explain that they have already obtained authorization to proceed with a clinical trial in which patients will undergo partially supervised exercise, thereby reducing the risk of errors in self-report data, much like the mice did. The trial, Kurz says, will be the first to look at immunological readings after exercise in pancreatic cancer, and the authors plan to initiate a subsequent trial testing the effects of the IL-15 superagonist. Both co-authors express cautious optimism about the prospect of improving treatments for this particularly difficult cancer.
“That’s really the part that’s extremely important,” says Bar-Sagi, “because now we find a modality, an exercise or a form of intervention, that seems to be able to work; it has a mechanism. It’s not that we just see in mice that tumors regress, but there’s a very good basis for something that might work.