Regnase-1敲除对脐血来源CAR-T细胞的生物学功能影响

The Effect of Regnase-1 Knockout on the Function of Cord Blood-Derived CAR-T Cells

嵌合抗原受体T(chimeric antigen receptor-T,CAR-T)细胞治疗虽然在血液肿瘤治疗中疗效显著,但仍面临CAR-T细胞体内持续性短的问题,后者与疗效密切相关。Regnase-1具有核糖核酸酶作用,负向调控免疫应答。该研究在脐血T(cord blood T)细胞上成功敲除Regnase-1,制备Regnase-1缺陷的靶向CD19的脐血CAR-T细胞Regnase-1-CAR-T,发现敲除Regnase-1不影响脐血T细胞表达CAR分子,也不影响CAR-T细胞体外增殖和分化,在CAR-T体外生长早期可显著抑制CD39耗竭分子,并且显著增强CAR-T特异性持续杀伤能力和扩增能力,有助于改善脐血CAR-T细胞持续性,为CAR-T细胞药物的优化奠定基础。

Although CAR-T(chimeric antigen receptor-T)cell therapy is effective in the treatment of hematologic tumors,it still faces the problem of short persistence of CAR-T cells in vivo,which is closely related to the clinical efficacy.Regnase-1 has a ribonuclease effect and negatively regulates the immune response.In this study,regnase1-deficient CAR-T cells delivered from cord blood T cells were prepared.The Regnase-1 deletion did not affect either the expression of CAR molecules of cord blood T cells or the proliferation or the differentiation of CAR-T cells in vitro.CD39,an exhausted T cell marker,could be significantly inhibited at the early stage of CAR-T growth in vitro.Regnase-1 kncokout enhanced the specific killing ability and increased amplication of CAR-T,which helps to improve cord blood-derived CAR-T cell persistence and lays a foundation for the optimization of CAR-T cell drugs.