PPARα Agonism Enhances Immune Response to Radiotherapy while Dietary Oleic Acid Results in Counteraction

Abstract Introduction: Head and neck cancer (HNC) improvements are stagnant, even with advances in immunotherapy. Our previous clinical trial data show altered fatty acid (FA) metabolism correlates with outcome. We hypothesized that pharmacologic and dietary modulation of FA catabolism will impact therapeutic efficacy. Methods: We performed in vivo and in vitro experiments employing PPARα agonism with fenofibrate (FF) or high oleic acid diets (OAD) with radiotherapy, generating metabolomic, proteomic, stable isotope tracing, extracellular flux analysis, and flow cytometric data to investigate these alterations. Results: FF improved anti-tumor efficacy of high dose per fraction radiotherapy in HNC murine models, while the OAD reversed this effect. FF treated mice on the control diet had evidence of increased FA catabolism. Stable isotope tracing showed less glycolytic utilization by ex vivo CD8+ T cells. Improved efficacy correlated with intratumoral alterations in eicosanoid metabolism and downregulated mTOR and CD36. Conclusion: Metabolic intervention with increased FA catabolism improves efficacy of HNC therapy and enhance anti-tumoral immune response.