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.

项目摘要收养细胞转移将靶向肿瘤的工程靶向细胞毒性T淋巴细胞（CTL）引入患者。尽管这种免疫疗法可有效防止血液系统恶性肿瘤，对应有的实体瘤无效免疫抑制微环境的一部分。肿瘤微环境提出了许多挑战 CTL能量产生，包括氧气和葡萄糖耗尽的环境以及抑制性肿瘤表达限制T细胞营养摄取的配体。这些条件使CTLS发育不良。幼稚的T细胞依靠在oxphos上进行能量。激活后，高度增殖物T细胞经历代谢重塑和转移从Oxphos转向糖酵解。因此，T细胞被认为是代谢塑性的大规模的代谢改变是T细胞发育的正常部分。但是，如何代谢改变撞击细胞命运和目标组织部位的功能仍然未知。这导致我们进入中心假设肿瘤部位的增强代谢可以防止CTL功能障碍并改善适应性细胞的转移免疫疗法结果。不幸的是，迄今为止，还没有直接检验该假设的方法。代谢重编程通常通过缺乏目标的全球药物进行研究选择性。我们的目标是通过我们的新型光遗传系统来规避这一限制，使我们能够直接调节T细胞代谢。我们将; （1）研究线粒体膜电位对CD8+的影响 T细胞效应子功能，（2）调节局部细胞因子信号以控制肿瘤中的T细胞代谢程序微环境和（3）发展深组织免疫调节方法。拟议的完成研究将使我们能够对免疫力进行全面分析，以提供有关T细胞如何如何提供新的见解与肿瘤微环境相互作用。