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针对REGNASE-1程序的长寿命T细胞进行癌症治疗

Jun Wei¹, Lingyun Long¹, Wenting Zheng²

¹Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.

|December 13, 2019

概括

向REGNASE-1将CD8+T细胞重新编程为长寿命的效应细胞,显著改善癌症免疫疗法. 这种方法增强了T细胞的持久性和功能,在临床前模型中提高了治疗效果.

科学领域:

免疫学
癌症生物学
分子生物学

背景情况:

采用细胞疗法 (ACT) 是一种有前途的癌症免疫疗法.
转移的T细胞的持久性和功能不足限制了ACT的疗效.

研究的目的:

确定增强T细胞持久性和功能以改善ACT的遗传点.
研究REGNASE-1在调节CD8+T细胞效应器功能和寿命方面的作用.

主要方法:

在体内组合CRISPR- Cas9突变性查以确定调节T细胞功能的基因.
二次基因组规模的CRISPR-Cas9查以确定下游目标.
在黑色素瘤和白血病小鼠模型中评估REGNASE-1缺乏的CD8+T细胞.

主要成果:

将REGNASE-1重编程的CD8+T细胞转化为具有增强积累,持久性和抗瘤功能的长寿命效应细胞.
在黑色素瘤和白血病小鼠模型中,REGNASE-1 缺乏显著改善治疗效果.
确定BATF是REGNASE-1的一个关键下游目标,它调节T细胞积累和线粒体适应性.
针对PTPN2和SOCS1等额外的因素进一步提高了REGNASE-1缺乏T细胞的疗效.

结论:

在抗瘤免疫中,REGNASE-1 是T细胞持久性和效应功能的关键调节者.
针对REGNASE-1和相关因子提供了一种改善癌症采用细胞治疗的新方法.
这些发现为提升基于T细胞的癌症治疗提供了途径.

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