Department of Pharmacy, Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
Center for Chemical Glycobiology, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China.
Mol Ther. 2024 Sep 4;32(9):3128-3144. doi: 10.1016/j.ymthe.2024.05.017. Epub 2024 May 11.
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.
支链氨基酸（BCAA）的改变，包括亮氨酸、异亮氨酸和缬氨酸，在晚期癌症患者中经常观察到。我们评估了嵌合抗原受体（CAR）T 细胞介导的癌细胞裂解在 BCAA 补充和缺失的免疫微环境中的疗效。BCAA 补充增加了癌细胞杀伤百分比，而加速 BCAA 分解代谢和降低 BCAA 转运体降低了癌细胞的裂解效果。因此，我们基于基因型和表型修饰，设计了 BCKDK 工程 CAR T 细胞，用于在肿瘤微环境中重新编程 BCAA 代谢。BCKDK 在 CAR-T 细胞中的过表达（OE）显著提高了癌细胞的裂解，而 BCKDK 敲除（KO）导致裂解潜能下降。在体内实验中，BCKDK-OE CAR-T 细胞治疗显著延长了 NALM6-GL 癌细胞荷瘤小鼠的存活时间，中央记忆细胞的分化和外周循环中 CAR-T 细胞的比例增加。BCKDK-KO CAR-T 细胞治疗导致存活时间缩短和外周循环中 CAR-T 细胞比例下降。总之，BCKDK 工程 CAR-T 细胞表现出明显的表型，具有更高的抗癌效率。
