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

项目摘要/摘要 尽管治疗方面取得了进展，但2019年美国仍将有超过60万人死于癌症。预防癌症 消除癌症发展过程中可能出现的死亡和/或发病风险。因此，癌症 预防是应对癌症挑战的最有效方式。健康饮食被认为是 通过保持和提高免疫力来降低癌症风险是必不可少的，但最近的重要试验并未显示 这些补充剂的有益效果。消极的结果反映了机械性的知识鸿沟 饮食因素影响健康。此续订申请的目标是确定蜂窝和 上皮脂肪酸结合蛋白(E-FABP)促进n-3脂肪酸合成的分子机制 通过增强免疫细胞分化和抗肿瘤活性来介导肿瘤预防。数据收集于 上一个资金周期已成功地将E-FABP确立为一种新的宿主来源的癌症预防因子 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)， 包括可可油(富含饱和脂肪酸)、红花油(富含18：2亚油酸)、鱼油(富含 N-3FAs)，均可诱导相似程度的小鼠肥胖。然而，这些肥胖小鼠中的肿瘤生长 差异很大，可可油组增长最快，鱼油组增长最慢。在……里面 分析这些肥胖小鼠的免疫表型，我们发现了一个非典型的CD8+γδT细胞群体 特别是在鱼油组中表达上调。更有趣的是，鱼油饮食诱导CD8+γδT 缺乏E-FABP的小鼠的分化和抗肿瘤作用减弱，提示有一种新的分子 E-FABP介导的机制。因此，我们推测E-FABP的宿主表达起着关键作用 在n-3FA诱导的免疫细胞分化和抗肿瘤作用方面。提出了三个具体目标来 解决此续订申请中的核心假设。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。实验的目的是阐明 膳食n-3FAs摄入通过E-γδ调节CD8+CD8T细胞分化的分子机制 依赖于FABP的表观遗传重编程。具体目标2将描述E-FABP如何介导n-3FA- 诱导抗肿瘤活性。AIM 2的结果有望揭示E-FABP促进宿主抗肿瘤 通过靶向免疫细胞和肿瘤来源的上皮细胞来发挥活性。《特定目标3》将评估 靶向E-FABP与优化的n-3FA饮食是否能有效预防肿瘤。总而言之， 这项提案的成功完成将使E-FABP成为新的癌症预防目标，并已 健康饮食介导的癌症预防的重要机制和临床意义。

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.