Dietary restriction reprograms cancer-fighting immune cells to enhance anti-tumour immunity

Reducing calorie intake helps cancer-fighting immune cells do their jobs more effectively, reports a study by Van Andel Institute scientists and collaborators.

The findings lay the groundwork for developing dietary strategies to boost the effects of a powerful class of cancer immunotherapies.

Growing evidence suggests dietary restriction has anti-cancer effects but the 'why and how' are not well understood. Our new study reveals one way this relationship may work: by providing T cells, the soldiers of the immune system, with the right mix of nutrients to more effectively fight cancer. Additional research is needed but we are hopeful these insights can inform evidence-based dietary guidelines to improve the effectiveness of immune-based cancer treatments."

Russell Jones, Ph.D., chair of VAI's Department of Metabolism and Nutritional Programming and corresponding author of the study

Dietary restriction is an approach that reduces overall calorie intake while maintaining good nutrition. Lab studies by other researchers suggest that modest calorie restriction may improve immune and metabolic function and delay the onset of certain age-related diseases. Conversely, diets that are too restrictive can have significant negative effects, such as nutrient deficiencies, muscle loss and depression.

The study, conducted in mouse models and published today in Nature Metabolism, explored a low-fat, high-protein diet given once a day with 30%–50% fewer calories than usual. The results showed this lower calorie intake promoted the formation of ketones, which act as a cellular fuel T cells use to become more effective tumor fighters. Ketones also help T cells combat cancer longer by preventing cellular exhaustion.

Ketones are metabolic by-products that are regularly produced by the liver. Ketone levels rise when glucose, a sugar that serves as the primary power source for cells, is in short supply, such as during exercise or fasting.

Earlier research by Jones's lab found that T cells often prefer ketones to glucose because ketones can "reprogram" T cells to better address threats. T cells' ability to rely on different nutrients may be a biological failsafe that boosts the immune system when resources are limited, such as when a person's appetite is suppressed during illness.

But T cells aren't the only type of cell that can harness ketones. Earlier this year, a study by VAI's Evan Lien, Ph.D., revealed that cancer cells also can use ketones to fuel their growth. This raises an important question - if both T cells and cancer cells can use ketones, then how can we ensure only T cells benefit? Ongoing research in Jones's and Lien's labs aims to answer this question. For now, the findings add to an increasingly complex understanding of how different nutrients help or hinder cellular activity. They also underscore the immensely intricate relationship between diet and every system in the body. Lien is a co-author of today's study.

Although their new findings are exciting, Jones said, there are several important caveats. While the study demonstrates that reducing calorie intake supports T cell function, it does not suggest dietary restriction prevents or treats cancer. Additionally, people with cancer already face significant challenges in meeting nutritional needs, in part due to loss of appetite or nausea associated with treatment. More research is needed to clearly understand all the factors at play.

"Nutrition is never one-approach-fits-all," he said. "Our work is an important starting point for developing scientifically sound and adaptable diets that physicians can tailor to an individual's needs."

The team's next steps include exploring different diet and fasting combinations to see how they impact immune function. In the long-term, Jones envisions robust clinical trials to evaluate potential dietary strategies designed to boost the success of immunotherapies against cancer.