Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
Lewis-Singer Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
Cells. 2021 Sep 6;10(9):2334. doi: 10.3390/cells10092334.
The metabolic milieu of solid tumors provides a barrier to chimeric antigen receptor (CAR) T-cell therapies. Excessive lactate or hypoxia suppresses T-cell growth, through mechanisms including NADH buildup and the depletion of oxidized metabolites. NADH is converted into NAD by the enzyme NADH Oxidase (), which mimics the oxidative function of the electron transport chain without generating ATP. Here we determine if promotes human CAR T-cell metabolic activity and antitumor efficacy. CAR T-cells expressing have enhanced oxygen as well as lactate consumption and increased pyruvate production. renders CAR T-cells resilient to lactate dehydrogenase inhibition. But in vivo in a model of mesothelioma, CAR T-cell's expressing showed no increased antitumor efficacy over control CAR T-cells. We hypothesize that T cells in hostile environments face dual metabolic stressors of excessive NADH and insufficient ATP production. Accordingly, futile T-cell NADH oxidation by is insufficient to promote tumor clearance.
实体瘤的代谢微环境为嵌合抗原受体 (CAR) T 细胞疗法提供了障碍。过多的乳酸或缺氧通过 NADH 积累和氧化代谢物耗竭等机制抑制 T 细胞生长。NADH 被酶 NADH 氧化酶 () 转化为 NAD，它模拟电子传递链的氧化功能而不产生 ATP。在这里，我们确定是否促进人类 CAR T 细胞代谢活性和抗肿瘤功效。表达的 CAR T 细胞增强了氧气以及乳酸的消耗，并增加了丙酮酸的产生。使 CAR T 细胞对乳酸脱氢酶抑制具有抗性。但是在间皮瘤模型中体内，表达的 CAR T 细胞在抗肿瘤功效方面并未超过对照 CAR T 细胞。我们假设在恶劣环境中的 T 细胞面临过多 NADH 和不足的 ATP 产生的双重代谢应激。因此，通过无效的 T 细胞 NADH 氧化作用，不足以促进肿瘤清除。
