A superresolution image of a group of killer T-cells (green and red) surrounding a cancer cell (blue, centre). Image: US NIH.
On World Cancer Day this year, Tata Memorial Hospital in Mumbai, known in India for its cancer care facilities, announced that it would study the effects of yoga on breast cancer patients. While the association between exercise and recovery in cancer patients has been known since the 1990s, we know little about how this works on a molecular level.
A new study shows that the key might lie in activating certain immune cells. The study, conducted by Randall Johnson and his team from the Karolinska Institute in Stockholm, Sweden, and the University of Cambridge, was the culmination of three years of research on what makes exercise good for cancer patients.
They first established that exercise could indeed decrease the growth of tumours. They induced tumours in mice, mimicking breast cancer in humans, and separated them into two groups: one exercised on running wheels and one did not. After a few days, the tumours had shrunk in the group that exercised but not in the sedentary group.
When the researchers examined blood samples from the mice, two things had dramatically increased after exercise: immune cells known as CD8+ T-cells and a compound called lactic acid.
The team first looked into CD8+ T-cells, which defend against tumours and infections. Did increased levels after exercise mean that the cells were involved in reducing tumour growth? To test this, the team removed CD8+ T-cells from tumour-bearing mice and then made them exercise. This time, exercising could not shrink the tumours: removing the T-cells also removed the positive effects of exercise.
“Then we did what, to my mind, is the coolest experiment in the paper,” said Johnson. They made mice exercise, carefully took CD8+ T-cells from them, and transplanted the cells into another set of mice that had tumours but didn’t exercise. To the scientists’ delight, simply transplanting CD8+ T-cells from mice that had exercised could shrink tumours in sedentary mice.
“The T-cells themselves are coming in ‘trained,’ making them better anti-tumour T-cells,” Johnson said.
What was ‘training’ the T-cells, though? That’s when the team turned their attention to lactic acid. After an intense bout of exercise, lactic acid is what makes your muscles feel like they’re burning. In the bloodstream, it circulates as lactate, its ionic form.
To mimic this form and the levels attained after exercise, the researchers injected sodium lactate into sedentary mice that had tumours. As with the T-cells, they found that daily injections of sodium lactate could shrink tumours and improve survival in these mice.
The team now knew that, through exercise, both lactate and CD8+ T-cells could reduce tumour growth. But this still didn’t explain how the two effects were linked.
To answer this, the scientists first checked whether lactate could independently activate CD8+ T-cells – and found that it could. Next, they again injected mice with lactate, only this time they removed the CD8+ T-cells from the mice. Without the T-cells, lactate injections could no longer lessen tumour growth.
“This shows that it’s really the lactate affecting the T-cells and helping them achieve a better anti-tumour effect,” Johnson said.
The study fills an important gap in our understanding of how exercise and the related metabolite changes boost anti-tumour the activities of our immune cells.
This said, “My main concern is that people should not think that only exercise can cure cancer,” S.V. Chiplunkar, a former director of the Advanced Centre for Treatment, Research and Education in Cancer, Mumbai, and current head of its Cancer Immunology and Immunotherapy division, cautioned.
“A combination of immunotherapy with supervised exercise or yoga regimens may yield significant benefits, but this needs to be tested in a randomised clinical trial.” Chiplunkar wasn’t involved in the study.
And as with any good study, this one spawned more questions than it answered. “Future studies should address how lactate levels are modulated in cancer patients/mice models in response [to] exercise,” Rajender Motiani, an assistant professor and DBT/Wellcome Trust India fellow at the Regional Centre for Biotechnology, Faridabad, said.
“A recent study in elite athletes showed that lactate is utilised by a unique class of gut microbiome, enhancing endurance and performance. It would be worth examining gut microbiota changes in cancer patients in response to exercise.”
Johnson’s team is now working out how much exercise is needed to boost T-cell activity. For example, one question they’re asking is if one hour of intense exercise could be better than two hours of light exercise.
Meanwhile, Helene Rundqvist, the study’s lead author, has been involved in a clinical trial assessing the effects of exercise on breast cancer patients undergoing chemotherapy. The trial is still active and expected to be completed in 2022.
Sruthi Balakrishnan is a Bangalore-based science writer who is intrigued by all things biological.