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以CD28作为共激活信号的嵌合抗原受体T细胞可以避开CTLA4介导的免疫负调控

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发表于 2015-8-23 10:10:17 | 显示全部楼层 |阅读模式
Tumor-Targeted Human T CellsExpressing CD28-Based Chimeric Antigen Receptors Circumvent CTLA-4 Inhibitor
CD28作为共激活信号的嵌合抗原受体T细胞可以避开CTLA4介导的免疫负调控
Adoptive T cell therapy represents a promisingtreatment for cancer. Human T cells engineered to express a chimeric antigenreceptor (CAR) recognize and kill tumor cells in aMHC-unrestricted manner andpersist in vivo when the CAR includes a CD28 costimulatorydomain. However, theintensity of the CAR-mediated CD28 activation signal and its regulation by theCTLA-4 checkpoint are unknown.We investigated whether T cells expressingananti-CD19, CD3 zeta and CD28-based CAR (19-28z) displayed the same proliferationandanti-tumor abilities than T cells expressing a CD3 zeta-based CAR (19z1)costimulatedthrough the CD80/CD28, ligand/receptor pathway. Repeated in vitroantigen-specific stimulations indicated that 19-28z+T cells secreted higher levelsof Th1 cytokines and showedenhanced proliferation compared to those of 19z1+or19z1-CD80+T cells. In an aggressivepre-B cell leukemia model, mice treated with19-28z+T cells had 10-fold reduced tumor progression compared to those treatedwith 19z1+or 19z1-CD80+T cells. shRNA-mediatedCTLA-4 down-regulation in19z1-CD80+T cells significantly increased their in vivo expansion andanti-tumor properties, but had no effect in 19-28z+T cells. Our resultsestablishthat CTLA-4 down-regulation may benefit human adoptive T cell therapyand demonstratethat CAR design can elude negative checkpoints to better sustainT cell function.
爱康得生物编译
嵌合抗原受体CAR-T在体内可以识别并杀伤肿瘤细胞,且这一过程不依赖MHC分子。然而CAR分子介导的CD28信号激活的强度以及检查点CTLA4是否对其有调控作用尚不知晓。为了揭开这一谜题,作者以CD19作为靶标,构建了3种不同的CAR分子;19-28Z:以CD28作为共激活信号;19Z1:无共激活信号;19Z1-CD80T:无共激活信号,通过CD80/CD28相互作用激活T细胞,结果表明以CD28为共激活信号的19-28ZCAR-T细胞的增殖、细胞因子分泌以及小鼠体内抗肿瘤活性等方面均优于其他两种CAR分子。作者通过表达shRNA抑制CTLA4在重组T细胞中的表达,研究结果显示降低CTLA4的表达可以显著提高19Z-CD80T细胞的体外增殖速率以及抗肿瘤活性,但是未能改变19-28z+T细胞的上述特征。作者认为下调CTLA-419Z-CD80T中的表达有益于人类过继T细胞疗法的发展,但是CAR 分子的设计可以避开免疫检查点分子对CAR-T细胞的负调控,以更好地维持T细胞功能。

Tumor-Targeted Human T Cells Expressing CD28-Based Chimeric Antigen Receptors Ci.pdf

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