肿瘤细胞治疗研究
英文原题：CAR T-cell Entry into Tumor Islets Is a Two-Step Process Dependent on IFNγ and ICAM-1.
表达嵌合抗原受体（CAR）的 T 细胞过继转移对晚期 B 细胞恶性肿瘤已显示出显著的临床疗效，但对实体瘤尚未显示出疗效。
表达嵌合抗原受体（CAR）的T细胞过继转移，在晚期B细胞恶性肿瘤中显示出显著临床疗效，但在实体瘤中尚未取得同等成功。本研究采用荧光成像显微镜和离体实验，比较CD20 CAR T细胞和EGFR CAR T细胞接触恶性B细胞及癌细胞后的早期功能应答，包括迁移、Ca2+反应和细胞毒性。结果显示，CD20 CAR T细胞可迅速与靶细胞形成依赖ICAM-1的有效结合。相比之下，EGFR CAR T细胞最初仅与肿瘤细胞岛边缘的部分癌细胞相互作用；外周初始活化后，EGFR CAR T细胞逐渐向肿瘤细胞区域中心迁移。对这一两步进入过程的分析表明，活化CAR T细胞可通过IFN-γ依赖通路诱导肿瘤细胞上调ICAM-1。通过抗体或shRNA阻断ICAM-1/LFA-1相互作用，会阻止CAR T细胞在肿瘤细胞岛中富集。IFN-γ和ICAM-1对于CAR T细胞进入肿瘤细胞岛的必要性，对改进实体瘤CAR T细胞治疗具有重要意义。
Adoptive transfer of T cells expressing chimeric antigen receptors (CAR) has shown remarkable clinical efficacy against advanced B-cell malignancies but not yet against solid tumors. Here, we used fluorescent imaging microscopy and ex vivo assays to compare the early functional responses (migration, Ca 2+ , and cytotoxicity) of CD20 and EGFR CAR T cells upon contact with malignant B cells and carcinoma cells. Our results indicated that CD20 CAR T cells rapidly form productive ICAM-1-dependent conjugates with their targets. By comparison, EGFR CAR T cells only initially interacted with a subset of carcinoma cells located at the periphery of tumor islets. After this initial peripheral activation, EGFR CAR T cells progressively relocated to the center of tumor cell regions. The analysis of this two-step entry process showed that activated CAR T cells triggered the upregulation of ICAM-1 on tumor cells in an IFN -dependent pathway. The ICAM-1/LFA-1 interaction interference, through antibody or shRNA blockade, prevented CAR T-cell enrichment in tumor islets. The requirement for IFN and ICAM-1 to enable CAR T-cell entry into tumor islets is of significance for improving CAR T-cell therapy in solid tumors.
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