20 dec. 2024
Oswald B.M. et al. (BioRxiv)
Keywords
Ketolysis
Dietary restriction
Anti-tumoural immunity
Main Findings
Dietary restriction and other calorically limited diet regimes have been shown to limit tumour growth and alter immune function. However, whether the benefits of dietary restriction on limiting tumour growth are mediated via modulation of the immune response remains unknown. In this manuscript, the authors aim to identify dietary restriction's impact on the anti-tumour immune response.
The authors utilise a model of dietary restriction where mice are only provided with 50% of their average daily food intake per day which results in ~20% weight loss after 7 days. Mice on dietary restriction showed increased survival and reduced implanted tumour growth relative to mice provided food ad libitum in a CD8+ T-cell dependent manner. Dietary restriction promoted increased T-cell infiltration into tumours and altered tumour infiltrating lymphocyte (TIL) sub-populations including reduced exhausted CD8+ TILs. Even amongst exhausted (TOX+) CD8+ TILs, those derived from mice on dietary restriction showed skewing away from a conventional terminally exhausted phenotype towards a more effector-like phenotype featuring reduced PD-1 and increased LY108 expression. Further, mice on dietary restriction showed increased levels of ketones in both the tumour microenvironment and serum.
The authors further explored the mechanistic effects of dietary restriction on CD8+ T-cells using a Listeria monocytogenes infection model. OT-I T-cells were adoptively transferred to mice on dietary restriction or fed ad libitumbefore infection with ovalbumin (OVA) expressing L. monocytogenes. CD8+ T-cells collected 7 days post-infection from dietary-restricted mice showed increased oxygen consumption, ATP production and mitochondrial membrane potential suggesting increased mitochondrial metabolism. Notably, heavy isotope tracing with the ketone body, β-hydroxybutyrate (β-OHB) showed that CD8+ T-cells from mice on dietary restriction have increased capacity to utilise ketones for tricarboxylic acid (TCA) cycle metabolism. Double knockout of BDH1 and SCOT, two important enzymes for ketolysis resulted in CD8+ T-cells with a reduced capacity to utilise ketones for metabolism and impaired mitochondrial function. Further, dietary restriction of mice with T-cell specific BDH1/SCOT knockout fails to show significant anti-tumoural benefit. Together this suggests that dietary restriction increases systemic ketone levels, which drive ketolysis in CD8+ T-cells and promote anti-tumoural responses.
Limitations & Suggestions
The authors suggest chronic antigen stimulation promotes a cellular state that relies more heavily on ketones for cellular metabolism. However, the authors also utilise the OVA-expressing L. monocytogenes model for exploring the mechanisms through which dietary restriction promotes improved CD8+ T-cell responses, which depicts a more acute model of T cell derived immune responses. Perhaps an infection model where antigen is chronically presented and T cell exhaustion is more likely (e.g. LCMV clone 13) may be more relevant in the explored anti-tumour context.
The dietary restriction model used by the authors results in high levels of weight loss within 7 days. However, the dietary restriction regime in the tumour models is often continued out to 40+ days. Does the dietary restriction cause significant baseline changes in immune parameters? Does dietary restriction have negative impacts on other aspects of physiology, for instance mouse activity, cardiac function or resistance to different types of infection? Further, while the authors show that dietary restriction significantly alters the phenotype of CD8+ T-cells during OVA-expressing L. monocytogenes infection, does dietary restriction also affect disease outcomes in this model (e.g. bacterial loads)?
How exactly dietary restriction promotes altered anti-tumoural CD8+ T-cell fate and function is not fully explored. The authors indicate that dietary restriction promotes increased production of acetyl-CoA from ketones. Therefore, it would be of interest whether dietary restriction alters T-cell acetylation or other aspects of the epigenetic state.
The authors utilise a system where mice are primed with dietary restrictions before tumour implantation. However, therapeutically, dietary restriction (or alternatives) would begin post-diagnosis. Therefore, it would be important to understand whether dietary restriction provides benefits when tumours are already established.
Significance/Novelty
This study demonstrates that one of the key mechanisms through which dietary restriction limits tumour growth is via supporting CD8+ T-cell anti-tumoural responses. Further, they demonstrate that dietary restriction promotes a CD8+ T-cell metabolic state which favours the use of ketone bodies for central metabolism. This study provides a rationale for examining how dietary restriction or metabolic drugs such as GLP-1 agonists could be used in conjunction with immunotherapies to support better cancer patient outcomes.
Credit
Reviewed by Megan Teh and Dominik Tuechler as part of a cross-institutional journal club between the Vanderbilt University Medical Center (VUMC), the Max-Delbrück Center Berlin, the Ragon Institute Boston (Mass General, MIT, Harvard), the Medical University of Vienna and other life science institutes in Vienna.
The author declares no conflict of interest in relation to their involvement in the review.