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Targeting glycosylation of PD-1 to enhance CAR-T cell cytotoxicity.
Journal of Hematology & Oncology ( IF 28.5 ) Pub Date : 2019-11-29 , DOI: 10.1186/s13045-019-0831-5
Xiaojuan Shi 1, 2 , Daiqun Zhang 1, 2 , Feng Li 1, 2 , Zhen Zhang 1, 2 , Shumin Wang 1, 2 , Yujing Xuan 1, 2 , Yu Ping 1, 2 , Yi Zhang 1, 2, 3, 4
Affiliation  

Asparagine-linked (N-linked) glycosylation is ubiquitous and can stabilize immune inhibitory PD-1 protein. Reducing N-linked glycosylation of PD-1 may decrease PD-1 expression and relieve its inhibitory effects on CAR-T cells. Considering that the codon of Asparagine is aac or aat, we wondered if the adenine base editor (ABE), which induces a·t to g·c conversion at specific site, could be used to reduce PD-1 suppression by changing the glycosylated residue in CAR-T cells. Our results showed ABE editing altered the coding sequence of N74 residue of PDCD1 and downregulated PD-1 expression in CAR-T cells. Further analysis showed ABE-edited CAR-T cells had enhanced cytotoxic functions in vitro and in vivo. Our study suggested that the single base editors can be used to augment CAR-T cell therapy.

中文翻译:

靶向PD-1的糖基化以增强CAR-T细胞的细胞毒性。

天冬酰胺连接的(N-连接的)糖基化是普遍存在的并且可以稳定免疫抑制性PD-1蛋白。减少PD-1的N联糖基化可能会降低PD-1的表达并减轻其对CAR-T细胞的抑制作用。考虑到天冬酰胺的密码子是aac或aat,我们想知道是否可以通过改变糖基化残基来在特定位点诱导从a·t到g·c转化的腺嘌呤碱基编辑器(ABE)来减少PD-1抑制。在CAR-T细胞中 我们的结果表明,ABE编辑可改变CAR-T细胞中PDCD1的N74残基的编码序列,并下调PD-1的表达。进一步的分析表明,ABE编辑的CAR-T细胞在体外和体内均具有增强的细胞毒性功能。我们的研究表明,单碱基编辑器可用于增强CAR-T细胞疗法。
更新日期:2019-11-29
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