Dietary regulation of anti-tumor immunity through caloric restriction - ABSTRACT OVERALL OBJECTIVE: The food we eat can affect tumor growth. Yet, it is unclear whether diets that alter nutrient levels in the tumor microenvironment (TME) primarily impact cancer cells or instead impact immune cells that provide critical defense against tumor progression. We have found that reducing overall calorie intake by 30–50%, a dietary regimen known as caloric restriction, antagonizes tumor growth by boosting anti-tumor immunity. Caloric restriction profoundly impacts the fate and function of CD8 T cells in the TME, favoring the activity of tumor-controlling T effector (Teff) cells while minimizing the accumulation of dysfunctional or “exhausted” T (Tex) cells. By studying how caloric restriction steers CD8 T cells between effector and exhausted fates, we will identify novel diet-regulated mechanisms that underpin CD8 T cell- mediated anti-tumor immunity and thus gain mechanistic insight into the epigenetic, transcriptional, and metabolic networks that link diet, lipid metabolism, and cancer progression. HYPOTHESIS: That the availability of ketone bodies versus fatty acids in the TME is a critical determinant of anti-tumor immunity. Our preliminary data indicate that caloric restriction antagonizes tumor growth by boosting anti-tumor CD8 T cell responses. These effects are lost when CD8 T cells cannot process ketone bodies, providing a mechanistic link between diet-regulated nutrients (ketone bodies) and anti-tumor T cell function. While caloric restriction and other diets can increase circulating levels of ketone bodies, some of these diets also increase circulating levels of fatty acids, which we hypothesize can negate or diminish the positive impact of ketone bodies on anti-tumor immunity. Our working model is that the balance between circulating levels of ketone bodies and fatty acids impacts ketone body-dependent metabolism and epigenetic programming in CD8 T cells and, by proxy, the balance between functional Teff cells (providing anti-tumor immunity) and dysfunctional Tex cells (dampening anti-tumor immunity) in the TME. SPECIFIC AIMS: (1) Determine how dietary fats influence anti-tumor T cell responses in the context of caloric restriction; (2) Determine how caloric restriction differentially controls T cell metabolism in the TME; and (3) Define how caloric restriction influences CD8 T cell fate decisions in the TME. IMPACT: Upon completion, this proposed research will have determined the mechanisms by which caloric restriction boosts CD8 T cell-mediated anti-tumor immunity, not only increasing the function of Teff cells but also decreasing the accumulation of dysfunctional (or “exhausted”) Tex cells in the TME. Our work will have laid the groundwork for defining dietary interventions with the power to boost the efficacy of immune checkpoint inhibitors (ICI) and diminish and/or reverse cancer progression.
