Dietary trans-vaccenic acid enhances anti-tumor immunity

项目摘要/摘要： 尽管对饮食和癌症风险之间的关系进行了广泛的研究，或者许多“平衡”的营养疗法 由于希望让癌症患者在治疗和康复期间保持健康和强壮，人们对如何饮食知之甚少 物质会影响癌症。我们最近的工作支持一个新的概念，即乙酰乙酸酯，一种源于饮食的， 循环酮体和膳食补充剂硫酸软骨素作为信号分子和 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 也就是说：哪些循环中的饮食衍生物质--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 或减弱癌症的启动、进展或对抗癌治疗的反应，以及如何？我们就这样构建了 并进行两次初步筛选以确定影响血液化学(BC)的BCS 对免疫检查点抑制剂(ICIS)的反应。我们鉴定了反式痘苗酸(TVA；又名：(11E)-八位解码器- 11-烯酸)作为两个筛选结果的最佳候选者，不仅增强了T细胞的活性 但也“拯救”依赖PD-L1/PD-1的T细胞的耗竭。TVA是反式作用的主要形式 在母乳中富含脂肪酸，而在海洋中发现顺式疫苗酸(CVA)，它是TVA的立体异构体 沙棘油。TVA也普遍存在于包括牛奶和黄油在内的乳制品中。TVA相对稳定， 在人和小鼠体内，只有大约19%和12%的饮食TVA自然地转化为瘤胃酸。 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增强 CD8+T细胞的抗肿瘤免疫作用。从机制上讲，TVA具有细胞外信号转导功能和 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，我们发现了一种免疫抑制因子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作为一种 通过抑制GPR43增强CD8+T细胞活化的信号分子，从而增强抗肿瘤作用 豁免权。因此，TVA对T细胞的影响独立于PD-L1/PD1轴，为 评估TVA与免疫检查点治疗联合应用的潜在协同疗效 免疫疗法。三个具体目标包括：(1)检验饮食中TVA增强CD8+T细胞的假设 活性和随之而来的抗肿瘤免疫作为单一的药物，并具有协同效应与 ICIS；(2)检验膳食TVA通过GPCR-CREB显示细胞外信号功能的假设 轴的CD8+T细胞激活，并探索潜在的信号和表观遗传机制从时间， 综合机制研究；以及(3)检验TVA通过与GPR43竞争而减弱GPR43的假设 SCFA激动剂，并进行结构活性研究(SAR)以设计效率更高的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.