CD26 CAR-T细胞线粒体和糖酵解代谢谱减弱。

IF 2.9 4区 医学 Q3 IMMUNOLOGY
Xiaoying Zhu, Zhaodong Zhong, Fankai Meng, Ping Zou, Yong You, Qing Li, Xiaojian Zhu
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引用次数: 0

摘要

背景:肿瘤细胞和T细胞共同表达嵌合抗原受体T细胞(CAR-T细胞)的多个靶点,这些自身抗原可能在CAR-T细胞扩增过程中不断刺激CAR-T细胞。持续暴露于抗原被认为会导致T细胞的代谢重编程,代谢谱是决定细胞命运和CAR-T细胞效应功能的关键。然而,在CAR-T细胞生成过程中刺激自身抗原是否可以重塑代谢谱尚不清楚。在这项研究中,我们的目的是研究CD26 CAR-T细胞的代谢特性,CD26 CAR-T细胞本身表达CD26抗原。方法:通过线粒体含量、线粒体DNA拷贝数和参与线粒体调控的基因,评价CD26和CD19 CAR-T细胞扩增过程中线粒体的生物发生情况。通过ATP的产生、线粒体质量和代谢相关基因的表达来研究代谢谱。此外,我们通过记忆相关标记物评估了CAR-T细胞的表型。结果:我们报道了CD26 CAR-T细胞在早期扩张阶段线粒体生物发生、ATP产生和氧化磷酸化水平升高。而线粒体的生物发生、线粒体质量、氧化磷酸化和糖酵解活性均在扩张后期减弱。相反,CD19 CAR-T细胞没有表现出这样的特征。结论:CD26 CAR-T细胞在扩增过程中表现出独特的代谢谱,这对细胞的持久性和功能极为不利。这些发现可能为CD26 CAR-T细胞在代谢方面的优化提供新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
CD26 CAR-T cells have attenuated mitochondrial and glycolytic metabolic profiling.

Background: Multiple targets of chimeric antigen receptor T cells (CAR-T cells) are shared expressed by tumor cells and T cells, these self-antigens may stimulate CAR-T cells continuously during the expansion. Persistent exposure to antigens is considered to cause metabolic reprogramming of T cells and the metabolic profiling is critical in determining the cell fate and effector function of CAR-T cells. However, whether the stimulation of self-antigens during CAR-T cell generation could remodel the metabolic profiling is unclear. In this study, we aim to investigate the metabolic characteristics of CD26 CAR-T cells, which expressed CD26 antigens themselves.

Methods: The mitochondrial biogenesis of CD26 and CD19 CAR-T cells during expansion was evaluated by the mitochondrial content, mitochondrial DNA copy numbers and genes involved in mitochondrial regulation. The metabolic profiling was investigated by the ATP production, mitochondrial quality and the expression of metabolism-related genes. Furthermore, we assessed the phenotypes of CAR-T cells through memory-related markers.

Results: We reported that CD26 CAR-T cells had elevated mitochondrial biogenesis, ATP production and oxidative phosphorylation at early expansion stage. However, the mitochondrial biogenesis, mitochondrial quality, oxidative phosphorylation and glycolytic activity were all weakened at later expansion stage. On the contrary, CD19 CAR-T cells did not exhibit such characteristics.

Conclusion: CD26 CAR-T cells showed distinctive metabolic profiling during expansion that was extremely unfavorable to cell persistence and function. These findings may provide new insights for the optimization of CD26 CAR-T cells in terms of metabolism.

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来源期刊
CiteScore
5.40
自引率
0.00%
发文量
133
审稿时长
4-8 weeks
期刊介绍: The journal Immunopharmacology and Immunotoxicology is devoted to pre-clinical and clinical drug discovery and development targeting the immune system. Research related to the immunoregulatory effects of various compounds, including small-molecule drugs and biologics, on immunocompetent cells and immune responses, as well as the immunotoxicity exerted by xenobiotics and drugs. Only research that describe the mechanisms of specific compounds (not extracts) is of interest to the journal. The journal will prioritise preclinical and clinical studies on immunotherapy of disorders such as chronic inflammation, allergy, autoimmunity, cancer etc. The effects of small-drugs, vaccines and biologics against central immunological targets as well as cell-based therapy, including dendritic cell therapy, T cell adoptive transfer and stem cell therapy, are topics of particular interest. Publications pointing towards potential new drug targets within the immune system or novel technology for immunopharmacological drug development are also welcome. With an immunoscience focus on drug development, immunotherapy and toxicology, the journal will cover areas such as infection, allergy, inflammation, tumor immunology, degenerative disorders, immunodeficiencies, neurology, atherosclerosis and more. Immunopharmacology and Immunotoxicology will accept original manuscripts, brief communications, commentaries, mini-reviews, reviews, clinical trials and clinical cases, on the condition that the results reported are based on original, clinical, or basic research that has not been published elsewhere in any journal in any language (except in abstract form relating to paper communicated to scientific meetings and symposiums).
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