Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Department of Dermatology and the Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
Cancer Lett. 2021 Mar 1;500:107-118. doi: 10.1016/j.canlet.2020.12.004. Epub 2020 Dec 5.
Therapeutic efficacy of chimeric antigen receptor (CAR) T cells is associated with their expansion, persistence and effector function. Although CAR T cell therapy has shown remarkable therapeutic effects in hematological malignancies, its therapeutic efficacy has been limited in some types of cancers - in particular, solid tumors - partially due to the cells' inability to persist and the acquisition of T cell dysfunction within a harsh immunosuppressive tumor microenvironment. Therefore, it would be expected that generation of CAR T cells with intrinsic properties for functional longevity, such as the cells with early-memory phenotypes, could beneficially enhance antitumor immunity. Furthermore, because the metabolic pathways of CAR T cells help determine cellular differentiation and lifespan, therapies targeting such pathways like glycolysis and oxidative phosphorylation, can alter CAR T cell fate and durability within tumors. Here we discuss how reprogramming of CAR T cell metabolism and metabolic switch to memory CAR T cells influences their antitumor activity. We also offer potential strategies for targeting these metabolic circuits in the setting of adoptive CAR T cell therapy, aiming to better unleash the potential of adoptive CAR T cell therapy in the clinic.
嵌合抗原受体 (CAR) T 细胞的治疗效果与其扩增、持久性和效应功能有关。尽管 CAR T 细胞疗法在血液系统恶性肿瘤中显示出了显著的治疗效果，但在某些类型的癌症中——特别是实体瘤——其治疗效果受到了限制，部分原因是细胞无法在恶劣的免疫抑制肿瘤微环境中持续存在和获得 T 细胞功能障碍。因此，人们期望产生具有内在功能长寿特性的 CAR T 细胞，例如具有早期记忆表型的细胞，这可能有益于增强抗肿瘤免疫。此外，由于 CAR T 细胞的代谢途径有助于决定细胞的分化和寿命，因此针对糖酵解和氧化磷酸化等代谢途径的治疗方法可以改变 CAR T 细胞在肿瘤中的命运和持久性。在这里，我们讨论了 CAR T 细胞代谢的重编程以及代谢向记忆性 CAR T 细胞的转变如何影响其抗肿瘤活性。我们还提供了在过继性 CAR T 细胞治疗中靶向这些代谢回路的潜在策略，旨在更好地释放过继性 CAR T 细胞治疗在临床上的潜力。
