Frisch Andrew T, Wang Yiyang, Xie Bingxian, Yang Aaron, Ford B Rhodes, Joshi Supriya, Kedziora Katarzyna M, Peralta Ronal, Wilfahrt Drew, Mullett Steven J, Spahr Kellie, Lontos Konstantinos, Jana Jessica A, Dean Victoria G, Gunn William G, Gelhaus Stacy, Poholek Amanda C, Rivadeneira Dayana B, Delgoffe Greg M
Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Tsinghua University, Beijing, China.
Cell Metab. 2025 Apr 1;37(4):870-885.e8. doi: 10.1016/j.cmet.2024.12.007. Epub 2025 Jan 28.
Cellular therapies are living drugs whose efficacy depends on persistence and survival. Expansion of therapeutic T cells employs hypermetabolic culture conditions to promote T cell expansion. We show that typical in vitro expansion conditions generate metabolically and functionally impaired T cells more reliant on aerobic glycolysis than those expanding in vivo. We used dichloroacetate (DCA) to modulate glycolytic metabolism during expansion, resulting in elevated mitochondrial capacity, stemness, and improved antitumor efficacy in murine T cell receptor (TCR)-Tg and human CAR-T cells. DCA-conditioned T cells surprisingly show no elevated intratumoral effector function but rather have improved engraftment. DCA conditioning decreases reliance on glucose, promoting usage of serum-prevalent physiologic carbon sources. Further, DCA conditioning promotes metabolic flux from mitochondria to chromatin, resulting in increased histone acetylation at key longevity genes. Thus, hyperglycemic culture conditions promote expansion at the expense of metabolic flexibility and suggest pharmacologic metabolic rewiring as a beneficial strategy for improvement of cellular immunotherapies.
细胞疗法是一种生物药物，其疗效取决于持久性和存活率。治疗性T细胞的扩增采用高代谢培养条件来促进T细胞扩增。我们发现，典型的体外扩增条件会产生代谢和功能受损的T细胞，这些T细胞比体内扩增的T细胞更依赖有氧糖酵解。我们使用二氯乙酸（DCA）在扩增过程中调节糖酵解代谢，从而提高线粒体能力、干性，并改善小鼠T细胞受体（TCR）转基因和人嵌合抗原受体T（CAR-T）细胞的抗肿瘤疗效。令人惊讶的是，经DCA处理的T细胞在肿瘤内的效应功能并未提高，但其植入能力却有所改善。DCA处理降低了对葡萄糖的依赖，促进了血清中普遍存在的生理碳源的利用。此外，DCA处理促进了从线粒体到染色质的代谢通量，导致关键长寿基因处的组蛋白乙酰化增加。因此，高血糖培养条件以代谢灵活性为代价促进扩增，并表明药物代谢重编程是改善细胞免疫疗法的有益策略。
