Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes.
Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes.
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DOI：
10.3389/fimmu.2023.1121565
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发表时间：
2023
影响因子：
7.3
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中科院分区：
文献类型：
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基因工程嵌合抗原受体（CAR）T细胞可以治愈标准治疗方法难以治愈的癌症患者。迄今为止，过继性细胞疗法对实体瘤的效果较差，这主要是由于免疫细胞在免疫抑制性肿瘤微环境（TME）中的归巢和功能受损。细胞代谢在T细胞功能和存活中起关键作用，并且易于操纵。该手稿概述了CAR T代谢的已知方面，并描述了操纵CAR T代谢特征以产生更好的抗肿瘤反应的潜在方法。与细胞代谢谱相关的不同T细胞表型与改善的抗肿瘤应答相关。CAR T制造过程中的几个步骤适合于可以产生和维持有利的细胞内代谢表型的干预。例如，共刺激信号通过代谢重新布线来执行。在CAR T扩增期间或过继转移后在患者中全身使用代谢调节剂被描述为产生和维持代谢状态的潜在方法，所述代谢状态可以赋予改善的体内T细胞功能和持久性。扩增过程中的细胞因子和营养素选择可以定制，以产生具有更有利代谢特征的CAR T产物。总之，对CAR T细胞代谢及其操纵的更好理解有可能指导更有效的过继细胞疗法的开发。
Genetically engineered chimeric antigen receptor (CAR) T cells can cure patients with cancers that are refractory to standard therapeutic approaches. To date, adoptive cell therapies have been less effective against solid tumors, largely due to impaired homing and function of immune cells within the immunosuppressive tumor microenvironment (TME). Cellular metabolism plays a key role in T cell function and survival and is amenable to manipulation. This manuscript provides an overview of known aspects of CAR T metabolism and describes potential approaches to manipulate metabolic features of CAR T to yield better anti-tumor responses. Distinct T cell phenotypes that are linked to cellular metabolism profiles are associated with improved anti-tumor responses. Several steps within the CAR T manufacture process are amenable to interventions that can generate and maintain favorable intracellular metabolism phenotypes. For example, co-stimulatory signaling is executed through metabolic rewiring. Use of metabolic regulators during CAR T expansion or systemically in the patient following adoptive transfer are described as potential approaches to generate and maintain metabolic states that can confer improved in vivo T cell function and persistence. Cytokine and nutrient selection during the expansion process can be tailored to yield CAR T products with more favorable metabolic features. In summary, improved understanding of CAR T cellular metabolism and its manipulations have the potential to guide the development of more effective adoptive cell therapies.