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Dietary restriction promotes anti-tumor immunity via T cell mediated ketone body metabolism

ABSTRACT: Diet can shape immune function in vivo, but the molecular mechanism remains poorly defined. In this study, we investigated how a reduction in food intake (hereafter referred to as dietary restriction or DR) affects CD8+ T cell function in multiple models. We found that DR reduced tumor burden in mice in a CD8+ T cell-dependent manner, indicating that the anti-tumor effects of DR are mediated by the immune system. Consistent with this observation, DR increased CD8+ T cell effector function, including production of interferon-γ and granzyme B. Moreover, analysis of tumor infiltrating CD8+ T cells showed DR led to a decrease in markers of T cell exhaustion (PD1, TIM3, TOX) and an increase in markers of cell stemness (LY108, TCF1). In a model of Listeria infection, we further showed that DR enhances CD8+ T cell mitochondrial fitness and bioenergetic capacity, indicating that DR impacts both CD8+ T cell metabolism and effector function. Using stable isotope tracing, we identified that CD8+ T cells from mice on DR preferentially consumed the ketone body β-hydroxybutyrate (βOHB), which is elevated 3-fold in serum of in mice on DR relative to ad libitum-fed mice. Notably, the effects of DR on anti-tumor immunity were attenuated in conditional knockout mice in which T cells are unable to catabolize βOHB, supporting that DR enhances anti-tumor immunity, in part, through increasing βOHB availability and metabolism by T cells. Current and future studies are exploring the effects of DR on different immune cell populations within tumors to further delineate the mechanism(s) by which DR enhances the immune response in cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE267070 | GEO | 2025/01/28

REPOSITORIES: GEO

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