Control of GVHD and Leukemia Relapse by Targeting Cell Metabolism

 描述（由申请人提供）：同种异体骨髓移植（allo-BMT）是通过T细胞介导的移植物抗白血病（GVL）效应治疗恶性血液病的有效疗法，但同种异体T细胞也经常导致严重的移植物抗宿主病（GVHD）。由于移植物抗宿主病和肿瘤复发是两个主要的问题时，异基因骨髓移植被用作血液系统恶性肿瘤的治疗，我们的研究的广泛和长期的目标是防止移植物抗宿主病和肿瘤复发，这将大大提高异基因骨髓移植的治疗潜力。糖酵解和氧化磷酸化（OXPHOS）是细胞产生能量来源的腺苷三磷酸（ATP）的两条基本代谢途径。由于OXPHOS高效生成ATP，正常细胞在常氧条件下依赖OXPHOS获取ATP，只有在缺氧条件下才转换为糖酵解。然而，恶性细胞主要利用糖酵解来产生能量，即使在常氧条件下也是如此，称为有氧糖酵解。与恶性细胞类似，活化的T细胞也会转换为糖酵解以获得足够的能量。细胞代谢在T细胞活化、分化和功能发挥中起着关键作用，是GVHD发生的关键。因此，靶向T细胞代谢途径以控制GVHD最近已成为一种有趣的策略。然而，关于同种异体BMT下的T细胞代谢途径知之甚少。本项目的目的是了解T细胞移植到异基因受体后的代谢途径，并确定/验证T细胞代谢途径上控制GVHD和肿瘤复发的潜在靶点。核心假设是糖酵解中可能存在的某种代谢途径由致病性T细胞和恶性细胞（如白血病）共享，因此靶向该特定途径将控制T细胞介导的GVHD并防止白血病复发。为了确定T细胞代谢途径（目标1），我们将使用代谢组学技术来定义体内同种异体反应下T细胞的复杂生化过程，并确定代谢过程或产物作为特异性抑制T细胞同种异体反应的潜在靶点。使用Seahorse生物能量学方法，我们的初步研究表明，同种异体BMT后的T细胞显著增加有氧糖酵解，并且通过基因消融哺乳动物雷帕霉素靶蛋白（mTOR）来阻断糖酵解基本上预防了GVHD。因此，我们将进一步验证乙醇酸途径作为控制GVHD和白血病复发的潜在靶点（目的2）。使用同种异体BMT和白血病的临床前小鼠模型，我们将确定靶向乙醇酸途径是否有效控制GVHD和白血病复发。

 DESCRIPTION (provided by applicant): Allogeneic bone marrow transplantation (allo-BMT) is an effective therapy for hematologic malignancies through T cell-mediated graft-versus-leukemia (GVL) effects, but allogeneic T cells often lead to severe graft-versus-host disease (GVHD) as well. Because GVHD and tumor relapse are two major concerns when allo-BMT is used as a therapy for hematologic malignancies, the broad and long-term goal of our research is to prevent GVHD and tumor relapse, which would greatly enhance the therapeutic potential of allo-BMT. Glycolysis and oxidative phosphorylation (OXPHOS) are two basic cellular metabolic pathways to generate of adenosine-5'triphosphate (ATP) as a source of energy. Because OXPHOS generates ATP with high efficiency, normal cells rely on OXPHOS for ATP under normoxia conditions, and only switch to glycolysis under hypoxic conditions. However, malignant cells primarily utilize glycolysis for energy production even under normoxia conditions, known as aerobic glycolysis. Similar to malignant cells, activated T cells also switch to glycolysi to acquire sufficient energy. Cell metabolism plays a key role in T-cell activation, differentiatio and function, which is essential for the induction of GVHD. As a consequence, targeting T-cell metabolic pathways to control GVHD has recently become an interesting strategy. However, very little is known about T-cell metabolic pathways under allogeneic BMT. The objective of this project is to understand the metabolic pathways of T cells after being transplanted into allogeneic recipients, and to identify/validate potential targets on T-cell metabolic pathways in controlling GVHD as well as tumor relapse. The central hypothesis is that a certain metabolic pathway likely within glycolysis is shared by pathogenic T cells and malignant cells such as leukemia, and thus targeting this specific pathway will control T-cell mediated GVHD and prevent leukemia relapse. To determine T-cell metabolic pathways (Aim 1), we will use and metabolomics technology to define the complex biochemical processes of T cells under allogeneic responses in vivo, and to identify metabolic processes or products as potential targets to specifically inhibit T-cell allogeneic responses. Using Seahorse bioenergetics approach, our preliminary study has shown that T cells after allogeneic BMT dramatically increased aerobic glycolysis, and blocking glycolysis by genetically ablating mammalian target of rapamycin (mTOR) essentially prevented GVHD. Thus, we will further validate glycolic pathway as potential target in controlling GVHD and leukemia relapse (Aim 2). Using preclinical murine models of allogeneic BMT and leukemia, we will determine whether targeting glycolic pathway is effective in controlling GVHD and leukemia relapse.