Increasing Thiols for Improving T cell Immunotherapy

摘要 改进过继细胞治疗(ACT)方案的新策略正在涌现，以增强体内的持久性 过继转移肿瘤表位特异性T细胞，克服肿瘤诱导的免疫抑制。我们的 初步数据表明，长寿的中央记忆T细胞(Tcm)与 以及它们的抗氧化能力。硫氧还蛋白-1(TRX)的过表达，这是一个调节细胞- 表面硫醇(c-SH)增加TCR转基因小鼠T细胞的中医表型 Trx转基因小鼠，或用带有TCR和Trx的逆转录病毒载体工程人T细胞。这些 初步的观察结果使我们提出了这样的假设：“TRX的存在促使肿瘤反应性T细胞转化为c-SHHI。 表型，这导致氧化肿瘤微环境的持久性增加，并改善了肿瘤 我们建议进一步加强这一战略的翻译方面，方法是确定战略是否 在重组硫氧还蛋白(Rtrx)存在下增加抗氧化能力可重新编程肿瘤侵袭 并改善TIL介导的ACT。实验计划的具体目标如下：1) 确定人类肿瘤来源的TIL是否可以用Rtrx体外编程并表现出增强的抗 肿瘤表型，2)确定rtrx TIL在控制肿瘤生长方面是否优于传统TIL 活着。我们相信，我们的研究是创新的，将揭示需要考虑的基本方面。 当为ACT产生肿瘤特异性的中医/TSCM细胞时，通过减少 令人望而却步的成本。

ABSTRACT New strategies to improve adoptive cell therapy (ACT) protocols are 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 their anti-oxidant capacity. Overexpression of thioredoxin-1 (Trx), a critical molecule that regulates cell- surface thiols (c-SH), increased Tcm phenotype in T cells obtained from TCR transgenic mouse crossbred with Trx transgenic mouse, or engineering human T cells with a retroviral vector with TCR and Trx together. These preliminary observations led us to hypothesize that “the presence of Trx drives tumor-reactive T cells to a c-SHhi phenotype, which results in increased persistence in the oxidative tumor microenvironment and improved tumor control." We propose to further strengthen the translational aspect of this strategy by determining if strategies to increase anti-oxidant capacity in presence of recombinant thioredoxin (rTrx) can reprogram tumor-infiltrating lymphocytes and improve TIL-mediated ACT. The experiments are planned under the following specific aims: 1) To determine if human tumor-derived TILs could be ex vivo programmed with rTRx and exhibit enhanced anti- tumor phenotype, 2) To establish if rTrx TILs are superior to conventional TILs in controlling tumor growth in vivo. We believe that our studies are innovative and will uncover essential aspects that need to be considered when generating tumor-specific Tcm/Tscm cells for the ACT and enhance its wider use by decreasing the prohibitive costs.