Optical control of T cell metabolism

项目总结 过继细胞转移将工程化肿瘤靶向细胞毒性T淋巴细胞(CTL)引入患者。而当 这种免疫疗法对恶性血液病很有效，但对实体瘤无效，因为 部分原因是免疫抑制的微环境。肿瘤微环境给人类带来了许多挑战 CTL能量产生包括耗氧和葡萄糖消耗环境及对肿瘤表达的抑制 限制T细胞吸收营养的配体。这些情况使CTL反应迟钝。幼稚T细胞依赖于 在OxPhos上获取能量。在激活后，高增殖效应T细胞经历新陈代谢 重塑并将依赖从OxPhos转移到糖酵解。因此，T细胞被认为是代谢可塑性的 大量的代谢变化是T细胞发育的正常部分。然而，新陈代谢变化是如何 影响细胞在其目标组织部位的命运和功能尚不清楚。这就引出了我们的中心假设 促进肿瘤部位的新陈代谢可以防止CTL功能障碍和改善过继细胞转移 免疫治疗的结果。不幸的是，到目前为止，还没有直接检验这一假设的方法。 代谢重新编程通常是通过全球给药来研究的，这些药物缺乏靶向性。 选择性。我们的目标是通过我们的新型光遗传系统来绕过这一限制，这种系统允许我们直接 调节T细胞新陈代谢。我们将：(1)研究线粒体膜电位对CD8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，以及(3)开发深层组织免疫调节方法。完成拟议的 研究将使我们能够获得对免疫的全面分析，从而为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.