Optical control of T cell metabolism

T细胞代谢的光学控制

基本信息

批准号：
9910585
负责人：
Minsoo Kim
金额：
$ 21.6万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-13 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9910585
关键词：
Adoptive Cell Transfers Aerobic Antigens Binding CD8-Positive T-Lymphocytes Cell physiology Cells Cellular Metabolic Process Cellular immunotherapy Clinical Clonal Expansion Cytokine Signaling Cytotoxic T-Lymphocytes Effectiveness Energy-Generating Resources Engineering Environment Face Fatty Acids Functional disorder Generations Genetic Glucose Glutamine Glycolysis Goals Hematologic Neoplasms Homing Human IL2RA gene Immune Immune response Immunity Immunotherapy In Vitro Injectable Interleukin 2 Receptor Interleukin-2 Interphase Cell Ligands Light Lighting Location Malignant Neoplasms Mediating Membrane Potentials Metabolic Metabolic Control Metabolic Pathway Metabolism Mitochondria Modeling Mus Names Neoplasm Metastasis Nutrient Optics Outcome Oxidative Phosphorylation Oxygen Pathology Patients Pattern Pharmaceutical Preparations Production Proteins Proton Pump Reaction Regulatory T-Lymphocyte Research Resolution Series Signal Transduction Site Solid Neoplasm Specificity System T cell regulation T cell response T-Cell Development T-Lymphocyte Techniques Testing Tissues Treatment Efficacy Warburg Effect aerobic glycolysis angiogenesis cancer cell cancer immunotherapy chemokine chimeric antigen receptor T cells cytokine cytotoxicity design effector T cell flexibility immunoregulation improved in vivo insight mitochondrial membrane mitochondrial metabolism neoplastic cell novel optogenetics prevent programs remote control side effect soft tissue success tumor tumor growth tumor hypoxia tumor microenvironment tumor-immune system interactions uptake

项目摘要

PROJECT SUMMARY Adoptive cell transfer introduces engineered tumor-targeting cytotoxic T lymphocytes (CTLs) to patients. While this immunotherapy is effective against hematologic malignancies, it is ineffective against solid tumors due in part to the immunosuppressive microenvironment. The tumor microenvironment presents many challenges to CTL energy production including oxygen and glucose depleted environment and tumor expression of inhibitory ligands that limit nutrient uptake by T cells. These conditions render CTLs hypo-responsive. Naïve T cells rely on OxPhos for energy. Following activation, the highly proliferative effector T cell undergoes metabolic remodeling and shifts reliance from OxPhos to glycolysis. As such, T cells are considered metabolically plastic and massive metabolic alterations are a normal part of T cell development. However, how metabolic alterations impact cell fate and function at their target tissue sites remain unknown. This leads us to our central hypothesis that boosting metabolism at the tumor site can prevent CTL dysfunction and improve adoptive cell transfer immunotherapy outcomes. Unfortunately, to date there has been no means of testing this hypothesis directly. Metabolic reprogramming is commonly studied through the global administration of drugs that lack target selectivity. We aim to circumvent this limitation through our novel optogenetic systems that allow us to directly modulate T cell metabolism. We will; (1) investigate the impact of the mitochondrial membrane potential on CD8+ T cell effector functions, (2) regulate local cytokine signals to control T cell metabolic programs in the tumor microenvironment, and (3) develop deep tissue immunomodulation approaches. The completion of the proposed study will enable us to gain a comprehensive analysis of immunity that can provide new insight into how T cells interact with the tumor microenvironment.

项目概要过继细胞移植将工程化的肿瘤靶向细胞毒性 T 淋巴细胞 (CTL) 引入患者体内。这种免疫疗法对血液系统恶性肿瘤有效，但对实体瘤无效，因为肿瘤微环境给免疫抑制微环境带来了许多挑战。 CTL能量产生包括氧气和葡萄糖耗尽环境和肿瘤表达的抑制限制 T 细胞营养吸收的配体使 CTL 反应低下。激活后，高度增殖的效应 T 细胞会通过 OxPhos 获取能量。重塑并将依赖从 OxPhos 转向糖酵解因此，T 细胞被认为具有代谢可塑性。大量的代谢改变是 T 细胞发育的正常部分，然而，代谢改变是如何发生的呢？对靶组织位点的细胞命运和功能的影响仍然未知，这引导我们得出我们的中心假设。促进肿瘤部位的新陈代谢可以预防 CTL 功能障碍并改善过继细胞转移不幸的是，迄今为止还没有方法直接检验这一假设。代谢重编程通常通过缺乏靶点的药物的全球管理来研究我们的目标是通过我们新颖的光遗传学系统来规避这一限制，该系统使我们能够直接我们将调节 T 细胞代谢；(1) 研究线粒体膜电位对 CD8+ 的影响。 T细胞效应功能，（2）调节局部细胞因子信号，控制肿瘤内T细胞代谢程序微环境，以及（3）开发深层组织免疫调节方法的完成。研究将使我们能够对免疫进行全面分析，从而为 T 细胞如何发挥作用提供新的见解与肿瘤微环境相互作用。