Increasing Thiols for Improving T cell Immunotherapy

摘要 改进过继性细胞治疗（ACT）方案的新策略正在出现，以增强细胞内肿瘤的体内持久性。 过继性转移肿瘤表位特异性T细胞并克服肿瘤诱导的免疫抑制。我们 初步数据表明，长寿的中央记忆T细胞（Tcm） 以及它们的抗氧化能力。硫氧还蛋白-1（Trx）的过表达是调节细胞增殖的关键分子。 表面巯基（c-SH），从TCR转基因小鼠与TCR转基因小鼠杂交获得的T细胞中Tcm表型增加， Trx转基因小鼠，或用具有TCR和Trx的逆转录病毒载体工程化人T细胞。这些 初步观察使我们假设“Trx的存在驱动肿瘤反应性T细胞向c-SHhi转化， 表型，这导致在氧化肿瘤微环境中的持久性增加，并改善肿瘤 控制“我们建议进一步加强这一战略的翻译方面，确定是否有战略， 在重组硫氧还蛋白（rTrx）存在下增加抗氧化能力可以重编程肿瘤浸润 淋巴细胞和改善TIL介导的ACT。这些实验计划的具体目标如下：1） 为了确定人肿瘤来源的TIL是否可以用rTRx离体编程并表现出增强的抗肿瘤活性， 肿瘤表型，2）为了确定rTrx TILs在控制肿瘤生长方面是否上级常规TILs， vivo.我们相信，我们的研究是创新的，将揭示需要考虑的重要方面 当产生ACT的肿瘤特异性Tcm/Tscm细胞时， 高昂的成本。

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.