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

• 批准号: 10531896
• 负责人: Shikhar Mehrotra
• 金额: $ 50.12万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 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/10531896
• 关键词: Acids; Adoptive Cell Transfers; Adoptive Transfer; Antioxidants; Biological Markers; Cell surface; Cells; Citric Acid Cycle; Clinic; Clinical; Complement; Crossbreeding; Data; Development; Effectiveness; Ensure; Epigenetic Process; Epitopes; Event; Exhibits; FRAP1 gene; Generations; Glycolysis; Human; Human Engineering; Immunosuppression; Immunotherapy; Knockout Mice; Knowledge; Learning; 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; Population; Post-Translational Protein Processing; Property; Protocols documentation; Recombinants; Recurrent tumor; Reporting; Retroviral Vector; Role; Signaling Molecule; Stem cell pluripotency; 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; Transgenic Organisms; Treatment Efficacy; Tumor Immunity; alpha ketoglutarate; experimental study; glucose uptake; improved; in vitro activity; in vivo; innovation; inorganic phosphate; metabolic phenotype; mitochondrial membrane; mitochondrial metabolism; overexpression; programs; response; stem-like cell; subcutaneous; translational potential; tumor; tumor growth; tumor microenvironment

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.

摘要 目前正在出现改善过继性细胞治疗（ACT）方案的新策略，以增强体内细胞移植。 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 免疫抑制我们的初步数据表明，长寿与 中枢记忆T细胞（Tcm）及其抗氧化能力。硫氧还蛋白-1（Trx）的过表达， 调节细胞表面巯基（c-SH）的分子，导致从人外周血中获得的T细胞中Tcm表型增加。 TCR转基因小鼠与Trx转基因小鼠杂交，或用逆转录病毒工程化人T细胞 载体与TCR和Trx在一起。此外，Pmel与Pmel-Trx细胞内代谢物的定量 结果表明，磷酸戊糖途径（PPP）和三羧酸循环（TCA）的代谢产物 与Pmel相比，Pmel-Trx T细胞中中间α-酮戊二酸（α-KG）显著更高 细胞虽然PPP产生的还原性中间体对克服氧化应激很重要，但最近的研究表明， 有报道表明，α-KG在延长细胞寿命和调节多能性方面很重要。 干细胞这些初步的观察使我们假设“Trx的存在驱动肿瘤”。 反应性T细胞的c-SHhi表型，这不仅表现出增强的抗氧化表型，但调节 包括翻译后修饰和表观遗传稳定性在内的事件组合，导致 代谢适合的抗肿瘤T细胞”。我们提出了以下具体目标：1）确定 T细胞表面的巯基/硫氧还蛋白调节体内肿瘤反应性Tcm/Tscm细胞的产生，2） 为了确定T细胞中代谢途径和代谢物的变化如何调节T细胞的产生， 体内肿瘤反应性Tcm/Tscm，3）为了确定还原硫醇和/或代谢物的调节是否导致 产生具有功能记忆表型的肿瘤反应性TCR转导的人T细胞。我们认为 我们的研究是创新的，并将揭示在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。