Dietary Restriction Boosts Anti-Tumor Immunity by Fueling T Cell Metabolism
A new study published in Nature Metabolism reveals that reducing calorie intake can reprogram immune cells to more effectively fight cancer, potentially enhancing the effectiveness of immunotherapy. Researchers found that dietary restriction elevates ketone levels, providing an alternative energy source for immune cells and bolstering their ability to combat tumors.
An increased proliferation of cancer cells and reduced anticancer activity of the immune system collectively trigger tumor growth. Cytotoxic effector T cells are critical for restricting this progression, and cancer immunotherapy aims to harness their power. However, these vital cells often become functionally impaired due to the harsh conditions within the tumor microenvironment, leading to what is known as terminal exhaustion.
The study, conducted by researchers at the Van Andel Institute and collaborators, focused on understanding how dietary restriction – reducing caloric intake without malnutrition – impacts the functioning of these effector T cells. Their work demonstrates a surprising link between diet, metabolism, and immune response.
Dietary Restriction Revitalizes Immune Cells in Mice
Using a mouse model, the research team found that reducing daily calorie intake by 50% significantly increased the number of tumor-controlling effector T cells while simultaneously limiting the accumulation of exhausted T cells within the tumor. This effect was so pronounced that the tumor-suppressive benefits were lost in mice lacking functional T cells, underscoring their central role in this process.
“These findings highlight a central requirement for CD8+ T cells,” according to the study.
Ketone Bodies: The Metabolic Key to T Cell Function
The researchers discovered that the beneficial effects of dietary restriction were linked to elevated levels of ketone bodies – produced from fats when glucose is limited – in both the blood and tumor tissue. These ketone bodies then enhanced the tricarboxylic acid (TCA) cycle metabolism and mitochondrial bioenergetics within the T cells.
Previous research from the team had indicated that T cells actually prefer ketones over glucose, as these metabolic byproducts, particularly β-hydroxybutyrate, improve oxidative metabolism and mitochondrial function. In the current study, they demonstrated that T cells unable to metabolize ketone bodies exhibited metabolic deficits, premature exhaustion, and a failure to control tumor growth under dietary restriction.
“Increasing blood and tumour levels of ketone bodies under dietary restriction influence effector T cell fate within the tumor microenvironment, enhancing their expansion, preventing terminal exhaustion, and subsequently limiting cancer progression,” the study authors concluded.
Acetyl-CoA: Fueling the Fight Against Cancer
The study also pinpointed acetyl-CoA, a critical metabolite, as a key player in T cell function. Researchers observed approximately twofold higher levels of acetyl-CoA in T cells under dietary restriction, indicating a direct impact of diet on metabolic homeostasis. Chronic stimulation of T cell receptors further boosted acetyl-CoA production through ketone body oxidation, suggesting that dietary restriction enhances its availability by increasing systemic ketone body levels.
Researchers hypothesize that interventions – dietary or therapeutic – that increase acetyl-CoA production in T cells could potentially shift T cell differentiation away from exhausted states and towards more effective, tumor-fighting states.
Ketone Utilization and Metabolic Stress
The research suggests that T cells may preferentially utilize ketone bodies as an energy source to buffer against metabolic stress. Evidence indicates that mobilizing stored energy from adipose tissue to support ketone body production helps maintain acetyl-CoA production under challenging metabolic conditions.
Interestingly, the study also found that combining dietary restriction with therapeutic inhibition of programmed cell death protein 1 (PD-1) – a common immunotherapy approach – further enhanced anticancer effects by promoting the expansion of effector T cells. This suggests a synergistic relationship between diet and immunotherapy.
Human Data Hints at Translational Potential
Analysis of existing human tumor single-cell transcriptomic datasets revealed that exhausted CD8+ T cells across multiple solid cancers express gene signatures associated with ketone body metabolism. This finding supports the translational relevance of the mouse data, although it’s important to note that no dietary information was available for these patients.
While these preclinical findings are promising, researchers caution that further validation is needed in human clinical studies. Prolonged dietary restriction may not be appropriate for all cancer patients, and careful consideration of feasibility and safety is essential. However, these results offer a compelling rationale for exploring evidence-based nutritional guidelines to complement and enhance current cancer immunotherapy strategies.
