彭布罗利珠单抗
免疫疗法
程序性细胞死亡
T细胞
癌症研究
融合蛋白
细胞生物学
配体(生物化学)
体外
体内
生物
分子生物学
细胞凋亡
化学
免疫系统
受体
免疫学
生物化学
重组DNA
生物技术
基因
作者
Zhaoduan Liang,Yanyan Li,Ye F. Tian,Huanling Zhang,Wenxuan Cai,Anan Chen,Lin Chen,Yifeng Bao,Bo Xiang,Heping Kan,Yi Li
标识
DOI:10.1016/j.canlet.2019.01.016
摘要
Tumor cells can escape immune surveillance through the programmed cell death protein 1 (PD-1) axis suppressing T cells. However, we recently demonstrated that high-affinity variants of soluble human programmed death-ligand 1 (shPD-L1) could diminish the suppression. We propose that in comparison to the wild-type shPD-L1, the further affinity enhancement will confer the molecule with opposite characteristics that augment T-cell activation and immunotherapeutic drug potential. In this study, a new shPD-L1 variant, L3C7c, has been generated to demonstrate ∼167 fold greater affinity than wild-type hPD-L1. The L3C7c-Fc fusion protein demonstrated completely opposite effects of conventional PD-1 axis by promoting redirected T-cell proliferation, activation and cytotoxicity in vitro, as being slightly better than that of anti-PD1-Ab (Pembrolizumab). Moreover, L3C7c-Fc was more effective than Pembrolizumab in enhancing redirected T cells' ability to suppress Mel624 melanoma growth in vivo. As a downsized L3C7c-Fc variant, L3C7v-Fc improved the anti-tumor efficacy in vivo when combined with dendritic cell vaccines. In conclusion, our studies demonstrate that high-affinity hPD-L1 variants could be developed as the next generation reagents for tumor immunotherapy based on the blockade of the PD-1 axis.
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