Optical control of T cell metabolism

项目摘要 连续性细胞转移将工程化的肿瘤靶向细胞毒性T淋巴细胞（CTL）引入患者。而 这种免疫疗法对恶性血液病有效，但对实体瘤无效， 免疫抑制的微环境。肿瘤微环境给肿瘤治疗带来了许多挑战。 CTL能量产生包括氧和葡萄糖耗尽的环境和肿瘤表达的抑制 限制T细胞摄取营养的配体。这些条件使得CTL低应答。幼稚T细胞依赖于 OxPhos的能量。在活化后，高度增殖的效应T细胞经历代谢过程， 重塑并将依赖从OxPhos转移到糖酵解。因此，T细胞被认为具有代谢可塑性， 大量的代谢改变是T细胞发育的正常部分。然而，新陈代谢的改变 影响细胞在其靶组织部位的命运和功能仍然未知。这就引出了我们的中心假设 增强肿瘤部位的代谢可以防止CTL功能障碍并改善过继细胞转移 免疫治疗的结果。不幸的是，迄今为止还没有直接检验这一假设的手段。 代谢重编程通常通过缺乏靶向的药物的全球管理来研究 选择性。我们的目标是通过我们的新型光遗传学系统来规避这种限制， 调节T细胞代谢。我们将：（1）研究线粒体膜电位对CD8+细胞的影响。 T细胞效应器功能，（2）调节局部细胞因子信号以控制肿瘤中的T细胞代谢程序 微环境，和（3）开发深层组织免疫调节方法。完成建议 这项研究将使我们能够获得对免疫力的全面分析，这可以为T细胞如何 与肿瘤微环境相互作用。

PROJECT SUMMARY Adoptive cell transfer introduces engineered tumor-targeting cytotoxic T lymphocytes (CTLs) to patients. While this immunotherapy is effective against hematologic malignancies, it is ineffective against solid tumors due in part to the immunosuppressive microenvironment. The tumor microenvironment presents many challenges to CTL energy production including oxygen and glucose depleted environment and tumor expression of inhibitory ligands that limit nutrient uptake by T cells. These conditions render CTLs hypo-responsive. Naïve T cells rely on OxPhos for energy. Following activation, the highly proliferative effector T cell undergoes metabolic remodeling and shifts reliance from OxPhos to glycolysis. As such, T cells are considered metabolically plastic and massive metabolic alterations are a normal part of T cell development. However, how metabolic alterations impact cell fate and function at their target tissue sites remain unknown. This leads us to our central hypothesis that boosting metabolism at the tumor site can prevent CTL dysfunction and improve adoptive cell transfer immunotherapy outcomes. Unfortunately, to date there has been no means of testing this hypothesis directly. Metabolic reprogramming is commonly studied through the global administration of drugs that lack target selectivity. We aim to circumvent this limitation through our novel optogenetic systems that allow us to directly modulate T cell metabolism. We will; (1) investigate the impact of the mitochondrial membrane potential on CD8+ T cell effector functions, (2) regulate local cytokine signals to control T cell metabolic programs in the tumor microenvironment, and (3) develop deep tissue immunomodulation approaches. The completion of the proposed study will enable us to gain a comprehensive analysis of immunity that can provide new insight into how T cells interact with the tumor microenvironment.