Kirin Central Research Institute, Kirin Holdings Company, Ltd., 26-1, Muraoka-Higashi 2, Fujisawa, Kanagawa, 251-8555, Japan.
Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Commun Biol. 2024 Jun 4;7(1):685. doi: 10.1038/s42003-024-06297-0.
Memory T cells demonstrate superior in vivo persistence and antitumor efficacy. However, methods for manufacturing less differentiated T cells are not yet well-established. Here, we show that producing chimeric antigen receptor (CAR)-T cells using berbamine (BBM), a natural compound found in the Chinese herbal medicine Berberis amurensis, enhances the antitumor efficacy of CAR-T cells. BBM is identified through cell-based screening of chemical compounds using induced pluripotent stem cell-derived T cells, leading to improved viability with a memory T cell phenotype. Transcriptomics and metabolomics using stem cell memory T cells reveal that BBM broadly enhances lipid metabolism. Furthermore, the addition of BBM downregulates the phosphorylation of p38 mitogen-activated protein kinase and enhanced mitochondrial respiration. CD19-CAR-T cells cultured with BBM also extend the survival of leukaemia mouse models due to their superior in vivo persistence. This technology offers a straightforward approach to enhancing the antitumor efficacy of CAR-T cells.
记忆 T 细胞表现出优异的体内持久性和抗肿瘤功效。然而，制造分化程度较低的 T 细胞的方法尚未得到很好的建立。在这里，我们展示了使用小檗胺（BBM）制造嵌合抗原受体（CAR）-T 细胞，小檗胺是一种天然化合物，存在于中药小檗属植物中，可以增强 CAR-T 细胞的抗肿瘤功效。BBM 是通过使用诱导多能干细胞衍生的 T 细胞进行基于细胞的化合物筛选而鉴定的，从而提高了具有记忆 T 细胞表型的细胞活力。使用干细胞记忆 T 细胞进行的转录组学和代谢组学研究表明，BBM 广泛增强了脂质代谢。此外，添加 BBM 会下调 p38 丝裂原活化蛋白激酶的磷酸化，并增强线粒体呼吸。与 BBM 一起培养的 CD19-CAR-T 细胞还由于其优异的体内持久性而延长了白血病小鼠模型的存活时间。这项技术为增强 CAR-T 细胞的抗肿瘤功效提供了一种简单直接的方法。
