Center for Inflammation and Epigenetics, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA.
Center for Inflammation and Epigenetics, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA; Xiangya Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, P.R. China.
Mol Ther. 2018 Apr 4;26(4):963-975. doi: 10.1016/j.ymthe.2018.01.020. Epub 2018 Mar 2.
Chimeric antigen receptor (CAR)-modified T cell therapy has the potential to improve the overall survival of patients with malignancies by enhancing the effectiveness of CAR T cells. Precisely predicting the effectiveness of various CAR T cells represents one of today's key unsolved problems in immunotherapy. Here, we predict the effectiveness of CAR-modified cells by evaluating the quality of the CAR-mediated immunological synapse (IS) by quantitation of F-actin, clustering of tumor antigen, polarization of lytic granules (LGs), and distribution of key signaling molecules within the IS. Long-term killing capability, but not secretion of conventional cytokines or standard 4-hr cytotoxicity, correlates positively with the quality of the IS in two different CAR T cells that share identical antigen specificity. Xenograft model data confirm that the quality of the IS in vitro correlates positively with performance of CAR-modified immune cells in vivo. Therefore, we propose that the quality of the IS predicts the effectiveness of CAR-modified immune cells, which provides a novel strategy to guide CAR therapy.
嵌合抗原受体 (CAR)-修饰的 T 细胞疗法通过增强 CAR T 细胞的有效性，有可能改善恶性肿瘤患者的总生存率。精确预测各种 CAR T 细胞的有效性是当今免疫治疗中尚未解决的关键问题之一。在这里，我们通过量化 F-肌动蛋白、肿瘤抗原聚集、溶酶体（LG）极化和 IS 内关键信号分子的分布，来评估 CAR 介导的免疫突触（IS）的质量，从而预测 CAR 修饰细胞的有效性。在具有相同抗原特异性的两种不同 CAR T 细胞中，长期杀伤能力（而非常规细胞因子的分泌或标准的 4 小时细胞毒性）与 IS 的质量呈正相关。异种移植模型数据证实，体外 IS 的质量与 CAR 修饰免疫细胞在体内的性能呈正相关。因此，我们提出 IS 的质量可以预测 CAR 修饰免疫细胞的有效性，这为指导 CAR 治疗提供了一种新策略。
