Anti-oxidant and Metabolic Phenotype in Regulating Tumor Specific T cell Memory Response

抗氧化和代谢表型调节肿瘤特异性 T 细胞记忆反应

基本信息

批准号：
9917102
负责人：
Shikhar Mehrotra
金额：
$ 52.24万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
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：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917102
关键词：
Acids Adoptive Cell Transfers Adoptive Transfer Antioxidants Biological Markers Cell surface Cells Citric Acid Cycle Clinic Clinical Complement Data Development Effectiveness Ensure Epigenetic Process Epitopes Event Exhibits FRAP1 gene Generations Glycolysis Human Human Engineering Immunosuppression Immunotherapy Knockout Mice Knowledge Lead Longevity Malignant Neoplasms Measures Mediating Membrane Potentials Memory Metabolic Metabolic Pathway Metabolism Mouse Strains Mus Outcome Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Pathway interactions Patients Pentosephosphate Pathway Phenotype Play Population Post-Translational Protein Processing Property Protocols documentation Recombinants Recurrence Reporting Retroviral Vector Role Signaling Molecule Sulfhydryl Compounds Surface T cell differentiation T cell response T cell therapy T memory cell T-Cell Development T-Lymphocyte TXN gene Transcription Factor AP-1 Transgenic Mice Translations Treatment Efficacy Tumor Immunity alpha ketoglutarate experimental study glucose uptake improved in vitro activity in vivo innovation metabolic phenotype mitochondrial membrane mitochondrial metabolism overexpression pluripotency programs response stem cells stem-like cell subcutaneous tumor tumor growth tumor microenvironment

项目摘要

ABSTRACT New strategies to improve adoptive cell therapy (ACT) protocols are now emerging to enhance in vivo persistence of adoptively transferred tumor epitope specific T cells and overcome tumor-induced immunosuppression. Our preliminary data suggests that there is a direct correlation between the long-lived central memory T cells (Tcm) and its anti-oxidant capacity. Overexpression of thioredoxin-1 (Trx), a key molecule that regulates cell-surface thiols (c-SH), resulted in increased Tcm phenotype in T cells obtained from TCR transgenic mouse crossbred with Trx transgenic mouse, or engineering human T cells with retroviral vector with TCR and Trx together. Further, a quantification of the metabolites within Pmel vs. Pmel-Trx cells showed that metabolites from pentose-phosphate pathway (PPP) and tricarboxylic acid cycle (TCA) intermediate alpha-ketoglutarate (α-KG) were significantly higher in Pmel-Trx T cells as compared to Pmel cells. While reductive intermediates generated by PPP are important to overcome oxidative stress, recent reports have shown that α-KG is important in extending the cellular lifespan and regulating pluripotency of stem cells. These preliminary observations lead us to hypothesize that “the presence of Trx drives tumor reactive T cells to a c-SHhi phenotype, which not only exhibits enhanced anti-oxidant phenotype, but regulates a combination of events including post-translational modifications, and epigenetic stability that lead to metabolically fit anti-tumor T cells”. We propose the following specific aims: 1) To determine how the level of thiol/thioredoxin on the surface of T cells regulates the generation of tumor reactive Tcm/Tscm cells in vivo, 2) To determine how changes in the metabolic pathways and metabolites in T cells regulate the generation of tumor reactive Tcm/Tscm in vivo, 3) To determine if modulation of reduced thiols and/or metabolites results in generation of tumor reactive TCR transduced human T cells with functional memory phenotype. We believe that our studies are innovative and will uncover important aspects that need to be considered when generating tumor specific Tcm/Tscm cells for ACT.

抽象的改进过继细胞疗法 (ACT) 方案的新策略现已出现，以增强体内过继转移的肿瘤表位特异性 T 细胞的持久性并克服肿瘤诱导的我们的初步数据表明，长寿之间存在直接相关性。中枢记忆 T 细胞 (Tcm) 及其抗氧化能力，硫氧还蛋白-1 (Trx) 的过度表达是关键。调节细胞表面硫醇 (c-SH) 的分子，导致从 T 细胞中获得的 Tcm 表型增加 TCR 转基因小鼠与 Trx 转基因小鼠杂交，或用逆转录病毒改造人类 T 细胞载体与 TCR 和 Trx 一起此外，对 Pmel 与 Pmel-Trx 细胞内的代谢物进行定量。显示来自戊糖磷酸途径（PPP）和三羧酸循环（TCA）的代谢物与 Pmel 相比，Pmel-Trx T 细胞中的中间体 α-酮戊二酸 (α-KG) 显着更高虽然 PPP 产生的还原中间体对于克服氧化应激很重要，但最近报告表明，α-KG 对于延长细胞寿命和调节细胞的多能性非常重要这些初步观察使我们认识到“Trx 的存在驱动肿瘤”。反应性 T 细胞形成 c-SHhi 表型，不仅表现出增强的抗氧化表型，而且调节包括翻译后修饰和表观遗传稳定性在内的事件组合 “代谢适合的抗肿瘤 T 细胞”提出以下具体目标：1）确定 T 细胞的水平如何。 T细胞表面的硫醇/硫氧还蛋白调节体内反应性肿瘤Tcm/Tscm细胞的生成，2) 确定 T 细胞代谢途径和代谢物的变化如何调节 T 细胞的产生体内反应性肿瘤 Tcm/Tscm，3) 确定还原硫醇和/或代谢物的调节是否会导致我们相信，具有功能性记忆表型的肿瘤反应性 TCR 转导人类 T 细胞的产生。我们的研究具有创新性，将揭示生成时需要考虑的重要方面用于 ACT 的肿瘤特异性 Tcm/Tscm 细胞。