肿瘤细胞治疗研究
英文原题：Reprogramming of human γδ T cells by expression of an anti-CD19 TCR fusion construct (εTRuC) to enhance tumor killing.
Reprogramming of human γδ T cells by expression of an anti-CD19 TCR fusion construct (εTRuC) to enhance tumor killing.
γδ εTRuC T细胞的生成和应用可能成为癌症免疫治疗的一种新方法。
我们开发了一种针对αβ T细胞的新型嵌合抗原受体形式，其中识别肿瘤抗原的单链可变片段直接融合到T细胞受体上，称为T细胞受体融合构建体（TRuC）。在此，我们在原代γδ T细胞中表达抗CD19 εTRuC，这些细胞通过唑来膦酸（Zol）或刀豆蛋白A扩增。我们显示，所得的εTRuC γδ T细胞被重编程以更好地识别CD19阳性B细胞肿瘤，并且在Zol扩增细胞的情况下，还能在体外识别表达CD19的结肠腺癌衍生细胞系。这导致增强的肿瘤杀伤、激活标志物CD25的上调以及细胞因子的分泌。我们发现，刀豆蛋白A扩增细胞的转导效率优于Zol扩增细胞。我们的体外细胞毒性数据表明，Vδ2 T细胞比Vδ1 T细胞是更好的杀伤细胞。最后，添加维生素C促进了慢病毒转导后更大数量γδ T细胞的恢复，该转导用于表达εTRuC。总之，γδ εTRuC T细胞的生成和使用可能是癌症免疫治疗的一种新方法。
We have developed a new format of a chimeric antigen receptor for αβ T cells, in which the single-chain variable fragment recognizing the tumor antigen is directly fused to the T cell receptor, called T cell receptor fusion construct (TRuC). Here, we express an anti-CD19 εTRuC in primary γδ T cells that were expanded using zoledronate (Zol) or concanavalin A. We show that the resulting εTRuC γδ T cells were reprogrammed to better recognize CD19-positive B cell tumors and-in case of the Zol-expanded cells-a CD19-expressing colon adenocarcinoma-derived cell line in vitro. This resulted in enhanced tumor killing, upregulation of the activation marker CD25, and secretion of cytokines. We found that the transduction efficiency of the concanavalin A-expanded cells was better than the one of the Zol-expanded ones. Our in vitro cytotoxicity data suggest that the Vδ2 T cells were better killers than the Vδ1 T cells. Finally, addition of vitamin C promoted the recovery of larger γδ T cell numbers after lentiviral transduction, as used for the expression of the εTRuC. In conclusion, the generation and use of γδ εTRuC T cells might be a new approach for cancer immunotherapy.
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