By elevating ketone-driven energy pathways inside CD8+ T cells, dietary restriction steers them away from exhaustion and toward potent tumour-fighting states, unlocking stronger responses to immunotherapy in preclinical models.
Study: Dietary restriction reprograms CD8+ T cell fate to enhance anti-tumour immunity and immunotherapy responses. Image Credit: Corona Borealis Studio / Shutterstock
Reducing calorie intake in mouse tumour models improves anticancer immunity by enhancing metabolic and cytotoxic functions of specific immune cells, reports a new study published in the journal Nature Metabolism.
Impaired T Cells and Tumor Progression
An increased proliferation of cancer cells and reduced anticancer activity of the immune system collectively trigger tumor growth. Cytotoxic effector T cells are primary immune cells responsible for restricting tumor progression. Cancer immunotherapy with immune checkpoint inhibitors provides robust protection against various malignancies by promoting the expansion of these effector T cells.
Although playing a key role in controlling tumor growth, cytotoxic effector T cells are often subjected to functional impairment due to chronic exposure to tumor antigens and inflammatory conditions in the tumor microenvironment. These functionally impaired T cells are termed terminally exhausted T cells, and their accumulation in tumors ultimately leads to tumor progression.
T Cell Metabolism and Dietary Influence
The survival and activity of effector T cells are regulated by metabolism. Chronic antigen exposure promotes metabolic and mitochondrial instability in effector T cells, leading to functional impairment. Conversely, certain nutrients, such as ketone bodies and acetate, can support effector T cell functions by fueling mitochondrial metabolic pathways.
Diet is a major modifiable factor influencing nutrient levels in the tumor microenvironment. Dietary restriction is a type of dietary intervention that reduces caloric intake without malnutrition, increases lifespan, and delays the onset and progression of cancer. The anticancer activity of dietary restriction has been thought to depend on its ability to alter growth factor signaling and nutrient availability for cancer cells.
In the current study, Van Andel Institute researchers and collaborators sought to explore the immune system’s contribution to the anticancer effects of dietary restriction. Specifically, they analyzed dietary restriction, driven changes in effector T cell functioning, and their impact on tumor growth in a preclinical mouse model.
Dietary Restriction Enhances Effector T Cells
An established mouse model of dietary restriction was used in the study, in which daily calorie intake was reduced by 50% without altering the nutritional content. After seven days of dietary restriction, melanoma and breast cancers were induced in mice.
The analysis of immune functions in mice revealed that dietary restriction significantly increased the expansion of tumor-controlling effector T cells and limited the accumulation of terminally exhausted T cells in the tumor microenvironment. Importantly, the tumour-suppressive effects of dietary restriction were lost in mice lacking functional T cells, highlighting a central requirement for CD8+ T cells.
Ketone Bodies Boost T Cell Metabolism
Dietary restriction, mediated induction of anticancer activity in effector T cells was linked to elevated levels of ketone bodies in the blood and tumour tissue, which subsequently enhanced tricarboxylic acid (TCA) cycle metabolism and mitochondrial bioenergetics through T cell, intrinsic ketone body oxidation.
Ketone bodies are produced in the liver from fats and serve as an alternative energy source when glucose supply is limited, such as during fasting or exercise. The researchers have previously reported that T cells preferentially choose ketones over glucose because these metabolic byproducts, particularly β-hydroxybutyrate (a key ketone body), enhance oxidative metabolism in T cells under dietary restriction, leading to increased mitochondrial function and TCA cycle-dependent signaling, which are critical for the improved functioning of effector T cells.
In the current study, the researchers demonstrated that T cells that cannot metabolize ketone bodies exhibit metabolic deficits, undergo premature exhaustion, and fail to control tumor growth under dietary restriction.
Overall, these observations, together with the current study findings, suggest that 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.
Acetyl-CoA Availability Supports T Cell Function
Acetyl-CoA is a critical metabolite for the optimal functioning of effector T cells, and insufficient production of this metabolite leads to T cell terminal exhaustion. This study found approximately twofold higher levels of acetyl-CoA in T cells under dietary restriction, as demonstrated in antigen-specific effector CD8+ T cells in a mouse infection model used to study dietary restriction and conditioned T cell metabolism, indicating a direct impact of diet on acetyl-CoA homeostasis.
According to the study findings, chronic T cell receptor stimulation enhances acetyl-CoA production through ketone body oxidation, further suggesting that dietary restriction enhances acetyl-CoA availability by increasing systemic ketone body levels.
Based on these observations, researchers hypothesized that dietary interventions or therapeutics that increase acetyl-CoA production in T cells may control tumor growth by shifting T cell differentiation from terminally exhausted states towards effector-like states.
Ketone Utilization Buffers Metabolic Stress
Regarding remodeling of host metabolism under metabolically stressful conditions, evidence indicates that mobilization of stored energy from adipose tissue to support ketone body production facilitates the host’s maintenance of acetyl-CoA production. Given these observations, researchers hypothesize that T cells preferentially choose ketone bodies for energy to buffer against metabolic perturbations that negatively affect their functional integrity.
Notably, the study found that therapeutic inhibition of programmed cell death protein 1 (PD-1) enhanced anticancer effects of dietary restriction by promoting the expansion of effector T cells in mouse tumour models. These findings highlight the potential to improve the efficiency of cancer immunotherapy through dietary interventions.
Human Data Suggest Translational Relevance
Consistent with these findings, analyses of existing human tumour single-cell transcriptomic datasets revealed that effector-like exhausted CD8+ T cells across multiple solid cancers express gene signatures associated with ketone body metabolism, supporting the translational relevance of the mouse data, although no dietary information was available for these patients.
Overall, these findings from preclinical models may help inform evidence-based nutritional guidelines that complement or enhance current cancer immunotherapy strategies but require validation in human clinical studies and careful consideration of feasibility and safety, given that prolonged dietary restriction may not be appropriate for all cancer patients.