Krug Adrien, Martinez-Turtos Adriana, Verhoeyen Els
Université Côte d'Azur, INSERM, C3M, 06204 Nice, France.
CIRI, Université de Lyon, INSERM U1111, ENS de Lyon, Université Lyon1, CNRS, UMR 5308, 69007 Lyon, France.
Cancers (Basel). 2021 Dec 30;14(1):183. doi: 10.3390/cancers14010183.
Chimeric antigen receptor (CAR) T and CAR NK cell therapies opened new avenues for cancer treatment. Although original successes of CAR T and CAR NK cells for the treatment of hematological malignancies were extraordinary, several obstacles have since been revealed, in particular their use for the treatment of solid cancers. The tumor microenvironment (TME) is competing for nutrients with T and NK cells and their CAR-expressing counterparts, paralyzing their metabolic effective and active states. Consequently, this can lead to alterations in their anti-tumoral capacity and persistence in vivo. High glucose uptake and the depletion of key amino acids by the TME can deprive T and NK cells of energy and building blocks, which turns them into a state of anergy, where they are unable to exert cytotoxic activity against cancer cells. This is especially true in the context of an immune-suppressive TME. In order to re-invigorate the T, NK, CAR T and CAR NK cell-mediated antitumor response, the field is now attempting to understand how metabolic pathways might change T and NK responses and functions, as well as those from their CAR-expressing partners. This revealed ways to metabolically rewire these cells by using metabolic enhancers or optimizing pre-infusion in vitro cultures of these cells. Importantly, next-generation CAR T and CAR NK products might include in the future the necessary metabolic requirements by improving their design, manufacturing process and other parameters. This will allow the overcoming of current limitations due to their interaction with the suppressive TME. In a clinical setting, this might improve their anti-cancer effector activity in synergy with immunotherapies. In this review, we discuss how the tumor cells and TME interfere with T and NK cell metabolic requirements. This may potentially lead to therapeutic approaches that enhance the metabolic fitness of CAR T and CAR NK cells, with the objective to improve their anti-cancer capacity.
嵌合抗原受体（CAR）T细胞和CAR NK细胞疗法为癌症治疗开辟了新途径。尽管CAR T细胞和CAR NK细胞在治疗血液系统恶性肿瘤方面最初取得了非凡的成功，但此后也发现了一些障碍，尤其是在用于治疗实体癌方面。肿瘤微环境（TME）与T细胞和NK细胞及其表达CAR的对应细胞竞争营养物质，使它们的代谢有效状态和活跃状态瘫痪。因此，这可能导致它们的抗肿瘤能力和体内持久性发生改变。TME对葡萄糖的高摄取和关键氨基酸的消耗会使T细胞和NK细胞缺乏能量和构建模块，从而使它们进入无反应状态，无法对癌细胞发挥细胞毒性活性。在免疫抑制性TME的情况下尤其如此。为了重振T细胞、NK细胞、CAR T细胞和CAR NK细胞介导的抗肿瘤反应，该领域目前正试图了解代谢途径如何改变T细胞和NK细胞的反应及功能，以及它们表达CAR的伙伴的反应及功能。这揭示了通过使用代谢增强剂或优化这些细胞的体外预输注培养来对这些细胞进行代谢重编程的方法。重要的是，下一代CAR T细胞和CAR NK细胞产品未来可能会通过改进其设计、制造工艺和其他参数来纳入必要的代谢需求。这将克服由于它们与抑制性TME相互作用而导致的当前局限性。在临床环境中，这可能会与免疫疗法协同提高它们的抗癌效应活性。在这篇综述中，我们讨论肿瘤细胞和TME如何干扰T细胞和NK细胞的代谢需求。这可能潜在地导致增强CAR T细胞和CAR NK细胞代谢适应性的治疗方法，目的是提高它们的抗癌能力。
