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淘汰KLRC1克服了HLA-E介导的抑制,并改善了NK细胞对固体瘤的抗瘤活性

Alice Mac Donald^1,2, Delphine Guipouy^1,2, William Lemieux^1,2

¹Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montréal, QC, Canada.

Frontiers in immunology

|September 7, 2023

概括

在自然杀手 (NK) 细胞中对KLRC1基因进行CRISPR基因编辑,可以去除NKG2A免疫检查点. 这提高了NK细胞治疗对表达HLA-E的固体瘤的疗效.

科学领域:

免疫学免疫学免疫学
细胞疗法细胞疗法
癌症研究癌症研究

背景情况:

自然杀手 (NK) 细胞对于天生的免疫力至关重要,并且对现成的细胞疗法显示出前途.
固体瘤通常通过免疫抑制瘤微环境 (TME) 逃避NK细胞介导的杀死.
由KLRC1编码的NKG2A受体通过与HLA-E结合而作为NK细胞免疫检查点,HLA-E经常在瘤上过度表达,从而抑制NK细胞功能.

研究的目的:

通过使用CRISPR介导的KLRC1基因编辑来研究向NKG2A/HLA-E免疫检查点的有效性.
增强NK细胞对表达HLA-E的固体瘤的细胞毒性.

主要方法:

利用CRISPR介导的基因编辑来淘汰人类NK细胞中的KLRC1基因,产生KLRC1淘汰 (KLRC1 KO) NK细胞.
在实验室中评估NKG2A表达减少和NK细胞细胞毒性对HLA-E阳性瘤细胞系.
在HLA-E阳性转移性乳腺癌的异种小鼠模型中评估了KLRC1 KO NK细胞的治疗潜力.

主要成果:

KLRC1淘汰赛显著降低了NK细胞上的NKG2A表达 (81%的减少).
与野生型 (WT) NK细胞相比,KLRC1 KO NK细胞对多个HLA-E阳性固体瘤细胞系显著增强了细胞毒性.
在体内研究表明,采用 KLRC1 KO NK 细胞的转移显著延迟了瘤的进展,并改善了小鼠模型中的生存率.

结论:

KLRC1淘汰是一种有效的策略,可以克服NKG2A介导的抑制并增强NK细胞抗瘤活性.
这种方法有可能为固体瘤开发改进的NK细胞基础免疫疗法.
准NKG2A/HLA-E轴是用NK细胞疗法治疗固体瘤的一个有希望的途径.

关键词:

在HLA-E的基础上,HLA-E 在NKG2A中,NKG2A是NKG2A.细胞毒性细胞毒性这是一种抑制性受体抑制剂.自然杀手细胞是自然杀手细胞.固体瘤是一个固体瘤.

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