Effects of PGE2 on Reconstitution of Hematopoiesis and Immunity after UCBT

PGE2对UCBT后造血和免疫重建的影响

• 批准号: 8985871
• 负责人: VASSILIKI A BOUSSIOTIS
• 金额: $ 37.47万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-17 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8985871
• 关键词: Address; Affect; Antigens; Binding; Bioenergetics; Biological Models; CD8-Positive T-Lymphocytes; CD8B1 gene; Carnitine O-Palmitoyltransferase; Cell Differentiation process; Cell Therapy; Cells; Clinical; Cytomegalovirus; Development; Dimethyl Sulfoxide; Dinoprostone; Effector Cell; Employee Strikes; Enzymes; Epitopes; Fatty Acids; Funding; Gene Expression; Gene Expression Microarray Analysis; Generations; Genes; Glucose Transporter; Glycolysis; HLA A*0201 antigen; Hematopoiesis; Human; Human Herpesvirus 4; Immune; Immunity; In Vitro; Incidence; Individual; Life; Lipids; Mediating; Memory; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; NOD/SCID mouse; Pathway interactions; Phenotype; Property; Relapse; Solid Neoplasm; System; T cell differentiation; T memory cell; T-Lymphocyte; Transgenic Mice; Transgenic Organisms; Tumor Immunity; Umbilical Cord Blood Transplantation; Up-Regulation; WT1 gene; acyl-CoA oxidase; base; fatty acid oxidation; fatty acid transport; glucose uptake; gp100 Antigen; imprint; improved; improved functioning; in vivo; leukemia; leukemia treatment; lipid metabolism; melanoma; mortality; neoplasm immunotherapy; novel; novel strategies; oxidation; pathogen; programs; promoter; public health relevance; reconstitution; transcription factor; tumor

 DESCRIPTION (provided by applicant): The present revision application is based on the original RO1 application entitled "Effects of PGE2 on reconstitution of hematopoiesis and immunity after umbilical cord blood transplantation (UCBT)" (R01 CA183605-01). During the past 15 months we performed studies to investigate the effects of PGE2 in T cells. Using microarray gene expression analysis we determined that a number of genes were selectively altered by PGE2 in UCB T cells. The most striking effect was detected on the expression of the transcription factor NR4A2. NR4A transcription factors have recently emerged as regulators of metabolic function. Using ChIP-PCR, we found that PGE2-induced NR4A2 could bind on the promoter of carnitine palmitoyltransferase (CPT1A), the rate limiting enzyme of fatty acid transport to the mitochondria, resulting in upregulation of CPT1A and increased rate of fatty acid oxidation (FAO) in T cells. PGE2 also diminished the expression of the glucose transporter Glut 1 and the uptake of glucose and this effect was more prominent in CD8+ T cells. Using antigen-specific mouse CD8+ T cells and a model system of in vitro differentiation of T effector and T memory cells, we found that PGE2 promoted T memory cell differentiation. We also determined that PGE2 treatment of the UCB grafts had a significant clinical impact on pathogen-specific and tumor-specific immunity. Compared to control UCBT recipients, PGE2-UCBT recipients had significantly reduced incidence of EBV and CMV reactivation, and reduced incidence of leukemia relapse. Divergence in the metabolic reprogramming of T cells is critical to effectively imprint distinct T cell fates. It has been shown that metabolic switch to FAO promotes the conversion of CD8+ T effector to long-lived T memory cells. Enforcing FAO in various T cell experimental systems induced increased numbers of memory CD8+ T cells and resulted in the generation of memory precursors, TCM and TSCM cells, which display enhanced anti-tumor function. Taken together our in vitro findings on the effects of PGE2 on T cell metabolic reprogramming and T memory cell development, and our clinical observations of improved immunity in PGE2-UCBT recipients suggest that PGE2 treatment might improve anti-tumor immunity by mediating metabolic reprogramming of tumor-specific T cells. This approach might represent a novel method to generate potent tumor-specific T cells for cell based tumor immunotherapy. To address this hypothesis in this revision application we will pursue the following specific aim to: SA1: Determine the mechanisms of PGE2-mediated metabolic reprogramming and its effects on the generation and function of tumor-specific T cells. A) To determine the effects of PGE2 on the molecular, metabolic and gene expression programs of tumor- specific mouse T cells and on their anti-tumor function in vivo. B) To determine the effects of PGE2 on the molecular and metabolic and functional properties of tumor-specific human T cells.

 描述(由申请人提供)：本修订申请基于最初的RO1申请，题为“PGE2对脐带血移植后造血和免疫重建的影响”(R01 CA183605-01)。在过去的15个月里，我们进行了研究，以调查PGE2对T细胞的影响。通过基因表达谱分析，我们发现PGE2选择性地改变了脐带血T细胞中的一些基因。其中对转录因子NR4A2的表达影响最为显著。最近，NR4A转录因子作为代谢功能的调节因子出现。利用芯片-聚合酶链式反应发现，PGE2诱导的NR4A2能与脂肪酸转运到线粒体的限速酶肉碱棕榈酰转移酶(CPT1A)的启动子结合，导致CPT1A表达上调，增加T细胞的脂肪酸氧化速率(FAO)。PGE2还可降低葡萄糖转运蛋白GLUT 1的表达和葡萄糖的摄取，这种作用在CD8+T细胞中更为明显。利用抗原特异性小鼠CD8+T细胞和T效应细胞和T记忆细胞的体外分化模型系统，我们发现PGE2促进T记忆细胞的分化。我们还确定PGE2治疗的脐带血移植物对病原体特异性免疫和肿瘤特异性免疫有显著的临床影响。与对照UCBT接受者相比，PGE2-UCBT接受者EBV和CMV重新激活的发生率显著降低，白血病复发率降低。T细胞代谢重编程的差异是有效印记不同T细胞命运的关键。已有研究表明，代谢转换为FAO可促进CD8+T效应细胞向长寿命T记忆细胞的转化。在不同的T细胞实验系统中实施FAO可诱导CD8+T细胞数量增加，并产生具有增强抗肿瘤功能的记忆前体细胞--中药和中药细胞。总之，我们关于PGE2对T细胞代谢重编程和T记忆细胞发育的影响的体外研究结果，以及我们对PGE2-UCBT受者提高免疫力的临床观察表明，PGE2治疗可能通过介导肿瘤特异性T细胞的代谢重编程来提高抗肿瘤免疫能力。这种方法可能代表了一种新的方法来产生强大的肿瘤特异性T细胞，用于基于细胞的肿瘤免疫治疗。为了解决这一假设，在本修订应用中，我们将追求以下具体目标：SA1：确定PGE2介导的代谢重编程的机制及其对肿瘤特异性T细胞生成和功能的影响。1)研究前列腺素E_2对肿瘤特异性小鼠T细胞分子、代谢和基因表达程序的影响及其体内抗肿瘤功能。B)确定PGE2对肿瘤特异性T细胞的分子、代谢和功能特性的影响。