Harnessing oral acetate supplementation to enhance anti-tumor immunity

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Abstract for Administrative Supplement (The Office of Dietary Supplements) Mammals and their microbiota have co-evolved for millennia through periods of fluctuating or limited food availability. As such, restricting dietary intake could have the potential to restore our physiological state to one compatible with our evolutionary history. Consistent with this, mild or transient dietary restriction (DR) improves many aspects of health and aging. Emerging evidence from us and others has demonstrated that DR also optimizes the development and quality of immune responses. Therefore, our work has the potential to reveal unique, fundamental insights into the physiological factors and mechanisms involved in promoting optimal immune responses. Our primary goal is to harness these mechanisms in the design of novel cancer immunotherapies. New data from my laboratory (funded by parent R00 grant) indicate that enhanced immune function and host protection during DR is dependent on the gut microbiota. The microbiota is comprised of trillions of microorganisms that co-evolved with mammals and play a critical role in regulating host physiology, behavior, and immunity. Such effects can be mediated by microbiota-derived metabolites, such as the highly immunomodulatory short-chain fatty acids (SCFA). These include acetate, which has been shown to regulate immune responses via metabolic and epigenetic mechanisms. Thus, gut microbiota-derived metabolites provide a key link between dietary intake and immunoregulation. Our preliminary data suggest that acetate produced by the gut commensal Bifidobacteria is critical for optimizing immune function and host protection during DR. This finding led us to hypothesize that acetate supplementation alone will enhance anti-melanoma immune responses via metabolic and epigenetic mechanisms. To receive an Office of Dietary Supplements administrative supplement grant will be essential for us to address this question, and will significantly enhance the parent grant. In this proposal, we will use novel in vivo systems to directly test whether acetate supplementation promotes immune cell function by regulating 1) mitochondrial oxidative phosphorylation and 2) the expression of pro- inflammatory genes. Further, we will 3) harness acetate supplementation to optimize immunotherapy against established, solid tumors. The preliminary described here was acquired via funding from the parent grant, and the new proposed research objectives remains within the scope of this parent grant. Altogether, this proposal has the potential to promote a greater understanding of how dietary supplements can benefit health and be used to prevent and treat disease.