E-FABP mediates n-3 fatty acid-induced tumor prevention through epigenetic control of immune cell differentiation and function

项目总结/摘要 尽管治疗取得了进展，但2019年美国仍将有超过60万人死于癌症。预防癌症 消除了癌症发展中可能发生的死亡和/或发病的风险。因此，癌症 预防是应对癌症挑战的最有效途径。健康饮食被认为是 通过维持和提高免疫力来降低癌症风险至关重要，但最近的VITAL试验并未显示 这些补充剂的好处。消极的结果反映了机械的知识差距， 饮食因素调节健康。本更新申请的目的是确定蜂窝和 上皮脂肪酸结合蛋白（E-FABP）促进n-3脂肪酸- 通过增强免疫细胞分化和抗肿瘤活性介导的肿瘤预防。中收集的数据 上一个资助周期已经成功地将E-FABP作为一种新的宿主衍生的癌症预防因子， 非肥胖受试者。在我们的研究中，我们观察到不同类型的高脂肪饮食（HFD，45%脂肪）， 包括可可脂（富含饱和脂肪酸）、红花油（富含18：2亚油酸）、鱼油（富含 n-3FA），均在小鼠模型中诱导相似程度的肥胖。然而，这些肥胖小鼠的肿瘤生长 可可脂组生长最快，鱼油组生长最慢。在 通过分析这些肥胖小鼠的免疫表型，我们发现了一个非典型的CD 8 + γδ T细胞群， 在鱼油组中表达上调。更有趣的是，鱼油饮食诱导的CD 8 + γδ T细胞 在缺乏E-FABP的小鼠中，分化和抗肿瘤作用减弱，这表明一种新的分子 E-FABP介导的机制。因此，我们假设宿主E-FABP的表达在 在n-3 FA诱导的免疫细胞分化和抗肿瘤功能中。提出了三个具体目标， 解决这个更新申请中的核心假设。具体目标1将通过以下方式确定机制： E-FABP促进n-3FA诱导的免疫细胞分化。实验旨在阐明 饮食n-3 FAs的消耗通过E-调节CD 8 + γδ T细胞分化的分子机制 FABP依赖的表观遗传重编程具体目标2将描述E-FABP如何介导n-3 FA-1。 诱导的抗肿瘤活性。目的2的结果预期揭示E-FABP促进宿主抗肿瘤 通过靶向免疫细胞和肿瘤衍生的上皮细胞来发挥活性。第3章评价 用优化的n-3 FA饮食靶向E-FABP是否导致有效的肿瘤预防。总的来说， 该提案的成功完成将提供E-FABP作为新的癌症预防靶点， 对健康饮食介导的癌症预防具有重要的机制和临床意义。

PROJECT SUMMARY/ABSTRACT Despite therapeutic advances, over 600,000 people in the US will die from cancer in 2019. Preventing cancer eliminates the risk of mortality and/or morbidity that may occur with the development of cancer. Thus, cancer prevention represents the most effective way for addressing cancer challenges. Healthy diet is considered be essential to reduce cancer risk by maintaining and improving immunity, but recent VITAL trials did not show beneficial effects of these supplements. The negative results reflect the mechanistic knowledge gap of how dietary factors modulate health. The objectives of this renewal application are to determine cellular and molecular mechanisms by which epithelial fatty acid binding protein (E-FABP) promotes n-3 fatty acid- mediated tumor prevention by enhancing immune cell differentiation and anti-tumor activity. Data collected in the last funding cycle have successfully established E-FABP as a new host-derived cancer prevention factor in non-obese subjects. During our studies, we observed that different types of high fat diets (HFD, 45% fat), including cocoa butter (rich in saturated fatty acids, FAs), safflower oil (rich in 18:2 linoleic acid), fish oil (rich in n-3 FAs), all induced similar degree of obesity in mouse models. However, tumor growth in these obese mice was dramatically different with the fastest growth in cocoa butter group and slowest in the fish oil group. In analyzing the immunophenotype of these obese mice, we found an atypical population of CD8+ γδ T cells that was specifically upregulated in the fish oil group. More interestingly, fish oil diet-induced CD8+ γδ T differentiation and anti-tumor effects were blunted in mice lacking E-FABP, suggesting a novel molecular mechanism mediated by E-FABP. Thus, we hypothesized that host expression of E-FABP plays a critical role in n-3 FA-induced immune cell differentiation and anti-tumor function. Three specific aims are proposed to address the central hypothesis in this renewal application. Specific Aim 1 will determine the mechanisms by which E-FABP promotes n-3 FA-induced immune cell differentiation. Experiments are designed to elucidate molecular mechanisms by which consumption of dietary n-3 FAs regulate CD8+ γδ T cell differentiation via E- FABP-dependent epigenetic reprogramming. Specific Aim 2 will delineate how E-FABP mediates n-3 FA- induced anti-tumor activity. Results of Aim 2 are expected to reveal that E-FABP promotes host anti-tumor activity through targeting both immune cells and tumor-derived epithelial cells. Specific Aim 3 will evaluate whether targeting E-FABP with optimized n-3 FA diets results in effective tumor prevention. In summary, successful completion of this proposal will offer E-FABP as a new cancer prevention target and have significant mechanistic and clinical implications for healthy diet-mediated cancer prevention.