CISH deletion and IL-15 up-regulation of NK cell greatly improve its antitumor activity
Background IL-15 plays a crucial role in regulating the function of natural killer(NK)cells,while CISH acts as a negative regulator of the IL-15 signaling pathway,thereby affecting NK cell function.Gene editing targeting the CISH and IL-15 genes in NK cells has been shown to enhance their anti-tumor activity.Objective To investigate the effect of CISH gene and IL-15 gene on cytotoxicity of NK cells.Methods The CISH gene was disrupted using the AsCas12a Ultra gene editing tool,while the IL-15 gene was introduced to facilitate genetic modification of NK cells.The knockout efficiency of the CISH gene was assessed through gene sequencing,and the expression of IL-15 was measured via ELISA.Subsequently,the cytotoxicity of NK cells against H358 cell line post-gene editing was evaluated using LDH assay,and the impact of CISH knockout on IL-15-mediated anti-tumor function in NK cells was examined.Results The killing efficiency of the CISH gene knockout group and the CISH KO+IL-15 KI group was significantly enhanced compared to the control group(E:T=2:1 group,34.57%±6.32%vs71.40±5.81%and 69.23%±4.28%,P<0.001).Conclusion The knockout of the CISH gene can enhance the IL-15 signaling pathway and augment the anti-tumor activity of NK cells.
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