Impact of drugs targeting tumor metabolism on human CD8 T cell effector functions

与正常细胞相比，癌症和白血病细胞表现出强烈的葡萄糖和谷氨酰胺代谢升高，并改变了线粒体功能。对这些重要代谢途径的抑制会减少癌细胞的增殖和活性，并减少免疫抑制代谢物的分泌。然而，最近的研究表明，激活的免疫细胞，特别是T细胞的代谢表型与癌细胞相似。因此，应用被认为对两种细胞类型都必不可少的抑制代谢途径的药物可能会阻碍内源性和治疗性诱导的免疫反应，从而对患者预后产生不利影响。然而，CD8+T细胞的代谢和效应功能之间的相互作用还不是很清楚，特别是在人类系统中。在拟议的项目中，我们将首先详细描述原代人类CD8+T细胞亚群(幼稚、中央记忆、效应记忆)和体外产生的白血病反应性CD8+细胞毒性T淋巴细胞(CTL)的代谢表型。此外，我们还将分析双氯芬酸或单羧酸转运体1/2对糖酵解的抑制，二甲双胍或吡格列酮对线粒体的抑制，以及索拉非尼对上述CD8+T细胞的效应功能的影响。人类白血病反应性CD8+CTL对体内功能的影响将在携带白血病的NSG小鼠身上进行研究，主要集中在最有希望和临床相关的候选药物上。拟议项目的主要目标是详细描述代谢活性药物和人类CD8+T细胞功能之间的相互作用。这一结果应该能够识别免疫抑制的相互作用，也可以识别潜在的协同作用，以提高癌症治疗的有效性。

Cancer and leukemia cells display a strongly elevated glucose and glutamine metabolism and altered mitochondrial function compared to normal cells. The inhibition of those vital metabolic pathways diminishes the proliferation and viability of cancer cells and the secretion of immunosuppressive metabolites. Recent studies, however, suggest that the metabolic phenotype of activated immune cells, especially of T cells, shows similarities to that of cancer cells. Hence the application of drugs inhibiting metabolic pathways considered as essential for both cell types might impede endogenous and therapeutically induced immune responses, thereby adversely affecting patient outcome. However, the interaction between metabolism and effector functions of CD8+ T cells is not well elucidated, particularly in the human system. In the proposed project we will initially characterize the metabolic phenotype of primary human CD8+ T cell subsets (naïve, central memory, effector memory) and in vitro generated leukemia-reactive CD8+ cytotoxic T lymphocytes (CTL) in detail. Furthermore, we will analyze the impact of glycolytic inhibition by diclofenac or monocarboxylate transporter 1/2, mitochondrial inhibition by metformin or pioglitazone, and tyrosine kinase inhibition by sorafenib on effector functions of the aforementioned CD8+ T cell populations in vitro. The in vivo impact on effector functions of human leukemia-reactive CD8+ CTL will be investigated in leukemia bearing NSG mice, with main focus on the most promising and clinically relevant drug candidates. The major objective of the proposed project is the detailed characterization of the interaction between metabolically active drugs and human CD8+ T cell function. The results should allow the identification of immunosuppressive interactions but also potential synergisms in order to improve the effectivity of cancer therapies.