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独特的具有活性的CD4 CAR-T细胞对多种肿瘤细胞具有杀伤能力

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发表于 2016-1-26 20:51:10 | 显示全部楼层 |阅读模式
Individual Motile CD4(+) T Cells Can Participate in Efficient Multikilling through Conjugation to Multiple Tumor Cells.
T cells genetically modified to express a CD19-specific chimeric antigen receptor (CAR) for the investigational treatment of B-cell malignancies comprise a heterogeneous population, and their ability to persist and participate in serial killing of tumor cells is a predictor of therapeutic success. We implemented Timelapse Imaging Microscopy in Nanowell Grids (TIMING) to provide direct evidence that CD4(+)CAR(+) T cells (CAR4 cells) can engage in multikilling via simultaneous conjugation to multiple tumor cells. Comparisons of the CAR4 cells and CD8(+)CAR(+) T cells (CAR8 cells) demonstrate that, although CAR4 cells can participate in killing and multikilling, they do so at slower rates, likely due to the lower granzyme B content. Significantly, in both sets of T cells, a minor subpopulation of individual T cells identified by their high motility demonstrated efficient killing of single tumor cells. A comparison of the multikiller and single-killer CAR(+) T cells revealed that the propensity and kinetics of T-cell apoptosis were modulated by the number of functional conjugations. T cells underwent rapid apoptosis, and at higher frequencies, when conjugated to single tumor cells in isolation, and this effect was more pronounced on CAR8 cells. Our results suggest that the ability of CAR(+) T cells to participate in multikilling should be evaluated in the context of their ability to resist activation-induced cell death. We anticipate that TIMING may be used to rapidly determine the potency of T-cell populations and may facilitate the design and manufacture of next-generation CAR(+) T cells with improved efficacy.
独特的具有活性的CD4 CAR-T细胞对多种肿瘤细胞具有杀伤能力
表达CD19嵌合抗原修饰的T细胞为包含了异质种群的B细胞恶性肿瘤提供了一个调查性研究。并且他们的持续和参与连环杀灭肿瘤细胞的能力是治疗成功的可预测因素。我们实现了延时成像显微镜纳为网格(定时)技术,并提供直接证据:CD4+CAR-T细胞(CAR4细胞)通过同时结合多种肿瘤细胞发挥杀伤细胞能力。通过CAR4细胞和CAR8细胞的对比,说明了CAR4细胞能够参与杀伤和连环杀伤,他们这样做的速度较慢,可能是由于颗粒酶B的含量较低。在这两组细胞中,一个小亚群的单个细胞的高活力,表现出高效的单肿瘤细胞的杀伤能力。当共轭的孤立的单个肿瘤细胞存在时,T细胞以一个更高的频率快速凋亡,并且当CAR8 细胞存在时,这种效应更加明显。 我们的研究结果表明,CART细胞的能力与连环杀伤能力应该在他们抵抗活化诱导的细胞死亡的能力的背景下进行评估。我们预计,TIMING技术可用于快速确定T细胞群English,并可能有助于设计和制造的下一代CAR-T细胞与改进其疗效。
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