CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
BCKDK 修饰通过重编程支链氨基酸代谢增强 CAR-T 细胞的抗癌疗效
英文原题：BCKDK modification enhances the anticancer efficacy of CAR-T cells by reprogramming branched chain amino acid metabolism.
查看英文原题
BCKDK modification enhances the anticancer efficacy of CAR-T cells by reprogramming branched chain amino acid metabolism.
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中文摘要
晚期癌症患者常观察到支链氨基酸（BCAA）改变，包括亮氨酸、异亮氨酸和缬氨酸。本研究评估 BCAA 补充和缺失对免疫微环境中嵌合抗原受体（CAR）T 细胞介导癌细胞裂解能力的影响。补充 BCAA 提高癌细胞杀伤率；相反，加速 BCAA 分解代谢并减少 BCAA 转运体，会降低癌细胞裂解效能。
因此，研究者通过基因型和表型修饰设计工程化 BCKDK 的 CAR-T 细胞，以重编程肿瘤微环境中的 BCAA 代谢。CAR-T 细胞中过表达（OE）BCKDK 可显著提高癌细胞裂解；敲除（KO）BCKDK 则降低裂解能力。体内实验中，BCKDK-OE CAR-T 治疗显著延长携带 NALM6-GL 癌细胞小鼠的生存期，同时中央记忆细胞分化增加，外周血 CAR-T 比例升高。BCKDK-KO CAR-T 治疗则导致生存期缩短，外周血 CAR-T 比例降低。
总之，BCKDK 工程化 CAR-T 细胞呈现不同表型，并具有更强抗癌效能。
展开英文摘要原文
Altered branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are frequently observed in patients with advanced cancer.
We evaluated the efficacy of chimeric antigen receptor (CAR) T cell-mediated cancer cell lysis potential in the immune microenvironment of BCAA supplementation and deletion. BCAA supplementation increased cancer cell killing percentage, while accelerating BCAA catabolism and decreasing BCAA transporter decreased cancer cell lysis efficacy.
We thus designed BCKDK engineering CAR T cells for the reprogramming of BCAA metabolism in the tumor microenvironment based on the genotype and phenotype modification. BCKDK overexpression (OE) in CAR-T cells significantly improved cancer cell lysis, while BCKDK knockout (KO) resulted in inferior lysis potential.
In an in vivo experiment, BCKDK-OE CAR-T cell treatment significantly prolonged the survival of mice bearing NALM6-GL cancer cells, with the differentiation of central memory cells and an increasing proportion of CAR-T cells in the peripheral circulation. BCKDK-KO CAR-T cell treatment resulted in shorter survival and a decreasing percentage of CAR-T cells in the peripheral circulation.
In conclusion, BCKDK-engineered CAR-T cells exert a distinct phenotype for superior anticancer efficiency.
论文信息
- 作者
- Yang Q、Zhu X、Huang P、Li C、Han L、Han Y、Gan R、Xin B
- 第一作者单位
- Department of Pharmacy, Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.China
- 通讯作者单位
- Department of Pharmacy, Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China. Electronic address: guopharm@126.com.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Molecular therapy : the journal of the American Society of Gene Therapy2024 Sep 4
- 原文标识
- PubMed 38734897 · DOI 10.1016/j.ymthe.2024.05.017
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