Dietary trans-vaccenic acid enhances anti-tumor immunity

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Project Summary/Abstract: Despite extensive studies on relationships between diets and cancer risk, or many “balanced” nutrition therapies with hope to keep cancer patients healthy and strong for treatment and recovery, little is known about how dietary substances influence cancer. Our recent work supports a novel concept that acetoacetate, a diet-derived, circulating ketone body, and chondroitin sulfate, a dietary supplement, function as signaling molecules and selectively promote BRAF V600E-expressing tumor growth. This lays the foundation for our central question that is: which circulating diet-derived substances - defined as “blood chemicals”, commonly containing diet- derived nutrients including inorganics, organic metabolites, lipids, dietary supplements and proteins - potentiate or attenuate cancer initiation, progression or responses to anti-cancer therapies, and how? We thus constructed a “blood chemical (BC)” compound library and performed two preliminary screens to identify BCs that influence responses to immune checkpoint inhibitors (ICIs). We identified trans-vaccenic acid (TVA; a.k.a. (11E)-octadec- 11-enoic acid) as an “overlapping” top candidate from both screens, which not only enhances activation of T cells but also “rescues” PD-L1/PD-1-dependent exhaustion of T cells. TVA is the predominant form of trans- fatty acids enriched in human milk, while cis-vaccenic acid (CVA), a stereoisomer of TVA, is found in Sea Buckthorn oil. TVA is also commonly found in dairy products including milk and butter. TVA is relatively stable, and naturally only ~19% or 12% of dietary TVA is converted to rumenic acid in human or mice, respectively. Using diverse immunogenic and immunodeficient mouse models, we found that TVA, but not CVA, enhances anti-tumor immunity via CD8+ T cells. Mechanistically, TVA exhibits extracellular signaling function and enhances CD8+ T cell activation through a G-protein-coupled receptor (GPCR)-cAMP-responsive element binding protein (CREB) pathway. Moreover, we identified immunosuppressive GPR43, a short chain fatty acid (SCFA)-binding GPCR, as a target of TVA. Taken together, we hypothesize that dietary TVA functions as a signaling molecule to potentiate activation of CD8+ T cells by attenuating GPR43, leading to enhanced anti-tumor immunity. Thus, TVA’s effects on T cells are independent of the PD-L1/PD1 axis, providing a perfect rationale to evaluate potentially synergistic efficacy of TVA in combination with immune checkpoint therapy for an improved immunotherapy. Three specific aims include: (1) To test the hypothesis that dietary TVA enhances CD8+ T cell activity and consequent anti-tumor immunity as a single agent, and has synergistic effects in combination with ICIs; (2) To test the hypothesis that dietary TVA exhibits extracellular signaling function through a GPCR-CREB axis for CD8+ T cell activation, and explore the underlying signaling and epigenetic mechanisms by temporal, integrated mechanistic studies; and (3) To test the hypothesis that TVA attenuates GPR43 by competing with its SCFA agonists, and perform structure-activity research (SAR) to design TVA-derivatives with improved efficacy to target GPR43 and consequently activate CD8+ T cells.