Elucidating the role of the Branched Chain Aminotransferases (BCATc and BCATm) as novel metabolic checkpoints of anti-lymphoma T cell immunity

项目摘要 针对淋巴瘤的新免疫疗法在最近的临床试验中取得了令人鼓舞的结果。然而，在这方面， 这些疗法仅对一小部分缓解期较短的患者有效。的结果 这些研究表明在肿瘤微环境中存在免疫抑制。持续增 淋巴瘤微环境是淋巴瘤细胞和非恶性淋巴瘤细胞之间非常动态的网络。 可能促进肿瘤生长并因此产生耐药性的成分。T细胞代谢研究进展 已经证明T细胞在肿瘤微环境中经历代谢劣势，这通常 表现在T细胞耗竭，这危及它们破坏癌细胞的潜力。这表明， 探索新的（代谢）方法来提高T细胞的性能。我们的研究小组建议针对 支链氨基酸（BCAA）代谢作为T细胞活化的新代谢检查点， 淋巴瘤微环境我们的理论基础来自于这样的发现，即BCAA，亮氨酸， 对于T细胞活化，而BCAA代谢，由胞质（BCATc）和线粒体（BCATm）启动 支链氨基转移酶是一种将亮氨酸导向降解的方法。在这方面的目标 本申请的目的是确定BCATc和BCATm表达的丧失是否有利于持久性， 在我们创建的独特临床前小鼠模型中，淋巴瘤根除期间T细胞的功能完整性 实验室本申请的长期目标是提供新的手段来改善T细胞介导的免疫 反应，并解决T细胞驱动的抗淋巴瘤免疫疗法的挑战。中央 假设是由BCATm支持的BCATc通过被 T细胞活化的负反馈环调节的一部分。从T细胞中删除BCAT基因， 单独地或组合地，可以提供T细胞的代谢优势，允许它们保持活化 并成功地对抗淋巴瘤的生长。为了检验中心假设，我们确定了三个具体目标： (1)研究BCATc和BCATm的表达在T细胞亚群分化后如何变化，以及是否 BCAT蛋白对于T细胞谱系定型和功能是必不可少的，（2）确定阻断是否 在BCAA的转氨作用中增强T细胞对淋巴瘤肿瘤的反应，以及（3）研究是否 小鼠T细胞中BCATc表达的丧失可以克服淋巴瘤对抗CTLA 4治疗的抗性。 该项目的完成不仅将为改善目前的治疗方案提供机会， 淋巴瘤患者，但也将从事临床前癌症研究的学生。学生将受益匪浅。 从获得癌症的实践研究经验，这可以转化为增强的研究技能， 科学推理，更好地理解治疗方法。

PROJECT SUMMARY New immunotherapies targeting lymphomas delivered promising results during recent clinical trials. However, these therapies were only effective in a small subset of patients with short periods of remission. The results from these studies suggested the existence of immunosuppression in the tumor microenvironment. Indeed, the lymphoma microenvironment is a very dynamic network between lymphoma cells and non-malignant components that may promote tumor growth and consequently drug resistance. Progress in T cell metabolism has demonstrated that T cells experience a metabolic disadvantage in the tumor microenvironment, which often manifests in T cell exhaustion that jeopardizes their potential to destroy cancer cells. This reveals a critical need to explore new (metabolic) approaches to improve T cell performance. Our research team proposes to target the metabolism of the branched chain amino acids (BCAAs) as a novel metabolic checkpoint of T cell activation in the lymphoma microenvironment. Our rationale stems from the findings that the BCAA, leucine, is indispensable for T cells activation, while BCAA metabolism, initiated by the cytosolic (BCATc) and mitochondrial (BCATm) branched-chain aminotransferases, is a means to direct leucine toward degradation. The objective in this application is to determine whether a loss of expression of BCATc and BCATm is beneficial for the durability and functional integrity of T cells during lymphoma eradication in unique pre-clinical mouse models created in our laboratory. The long-term goal of this application is to provide new means to improve the T cell-mediated immune response and to address the challenges with T cell-driven anti-lymphoma immunotherapy. The central hypothesis is that BCATc, supported by BCATm, serves to provide checkpoint control on T cell function by being a part of a negative feedback loop regulation of T cell activation. Deletion of the BCAT genes from T cells, individually or in combination, may provide a metabolic advantage of T cells allowing them to remain activated and to successfully combat lymphoma growth. To test the central hypothesis, we identified three specific aims: (1) Investigate how the expression of BCATc and BCATm changes upon T cell subset differentiation and whether the BCAT proteins are essential for T cell lineage commitment and function, (2) Determine whether a blockage in the transamination of BCAAs enhances the T cell response to lymphoma tumors, and (3) Investigate whether a loss of expression of BCATc in mouse T cells can overcome the lymphoma resistance to anti-CTLA4 therapy. Completion of this project will not only provide the opportunity to improve the current treatment options for lymphoma patients but will also engage students in pre-clinical cancer studies. The students will highly benefit from acquiring hands-on research experience in cancer, which can be translated into enhanced research skills, scientific reasoning, and better understanding of treatment approaches.