Dietary trans-vaccenic acid enhances anti-tumor immunity

项目概要/摘要： 尽管有大量关于饮食和癌症风险之间关系的研究，或许多“平衡”营养疗法， 为了让癌症患者在治疗和康复过程中保持健康和强壮，人们对饮食如何影响癌症的治疗和康复知之甚少。 物质影响癌症。我们最近的工作支持了一个新的概念，乙酰乙酸，一种饮食衍生的， 循环酮体和膳食补充剂硫酸软骨素作为信号分子发挥作用， 选择性促进表达BRAF V600E的肿瘤生长。这为我们的中心问题奠定了基础 即：循环的饮食衍生物质-定义为"血液化学物质"，通常含有饮食- 衍生营养素，包括无机物、有机代谢物、脂质、膳食补充剂和蛋白质-增强 或减弱癌症的发生、进展或对抗癌疗法的反应，以及如何减弱？因此，我们构建了 "血液化学（BC）"化合物库，并进行了两次初步筛选，以确定影响 免疫检查点抑制剂（ICI）。我们鉴定了反式异油酸（TVA; a.k.a.（11 E）-十八碳- 11-烯酸）作为来自两种筛选的"重叠"最佳候选物，其不仅增强T 细胞，而且还"拯救" T细胞的PD-L1/PD-1依赖性耗竭。TVA是反式- 人乳中富含的脂肪酸，而顺式异油酸（CVA），TVA的立体异构体，在海中发现 沙棘油。TVA也常见于乳制品，包括牛奶和黄油。TVA相对稳定， 在人或小鼠中，自然地分别只有约19%或12%的膳食TVA转化为瘤胃酸。 使用不同的免疫原性和免疫缺陷小鼠模型，我们发现TVA，而不是CVA， 通过CD8 + T细胞的抗肿瘤免疫。在机制上，TVA表现出细胞外信号传导功能， 通过G蛋白偶联受体（GPCR）-cAMP反应元件增强CD8 + T细胞活化 结合蛋白（CREB）途径。此外，我们鉴定了免疫抑制性GPR43，一种短链脂肪酸， （SCFA）结合GPCR作为TVA的靶标。综上所述，我们假设饮食中的TVA起着 通过减弱GPR43来增强CD8 + T细胞的活化，导致增强的抗肿瘤作用。 免疫力因此，TVA对T细胞的作用不依赖于PD-L1/PD1轴，这为TVA的治疗提供了完美的理论基础。 评估TVA与免疫检查点疗法联合用于改善 免疫疗法三个具体的目的包括：（1）验证膳食TVA促进CD8 + T细胞增殖的假设 活性和随之产生的抗肿瘤免疫力，并且与 （2）验证膳食TVA通过GPCR-CREB发挥细胞外信号传导功能的假设 轴的CD8 + T细胞活化，并探讨潜在的信号转导和表观遗传机制， 综合机制研究;和（3）为了验证TVA通过与其竞争而减弱GPR43的假设， SCFA激动剂，并进行结构活性研究（SAR），以设计具有改善功效的TVA衍生物 靶向GPR43，从而激活CD8 + T细胞。

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.