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.

抽象的改善自适应细胞疗法（ACT）方案的新策略现在正在出现以增强体内适当转移的肿瘤表位特异性T细胞的持久性并克服了肿瘤诱导的免疫抑制。我们的初步数据表明，长寿之间存在直接相关中央记忆T细胞（TCM）及其抗氧化能力。硫氧还蛋白-1（TRX）的过表达，钥匙调节细胞表面硫醇（C-SH）的分子，导致TCM表型增加了T细胞中的TCM表型 TCR转基因小鼠用TRX转基因小鼠或逆转录病毒工程人T细胞杂交使用TCR和TRX的向量。此外，对PMEL与PMEL-TRX细胞中的代谢产物进行定量表明来自五磷酸五磷酸途径（PPP）和三碳酸周期（TCA）的代谢产物与PMEL相比细胞。虽然PPP产生的减少中间体对于克服氧化物应激很重要，但最近报告表明，α-kg对于延长细胞寿命和控制多能性很重要干细胞。这些初步观察结果使我们假设“ TRX的存在驱动肿瘤反应性T细胞对C-SHHI表型，该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的组合，导致代谢上拟合的抗肿瘤T细胞”。我们提出以下特定目的：1）确定如何确定 T细胞表面上的硫醇/硫氧还蛋白调节体内肿瘤反应性TCM/TSCM细胞的产生，2）确定T细胞中代谢途径和代谢产物的变化如何调节产生肿瘤反应性TCM/TSCM体内，3）确定降低硫醇和/或代谢物的调节是否导致肿瘤反应性TCR的产生用功能性记忆表型翻译了人类T细胞。我们相信我们的研究具有创新性，并将发现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。