肿瘤细胞治疗研究
英文原题：ZFP36 disruption is insufficient to enhance the function of mesothelin-targeting human CAR-T cells.
ZFP36 disruption is insufficient to enhance the function of mesothelin-targeting human CAR-T cells.
这些结果提示，单独破坏 ZFP36 不足以改善其功能，可能受益于多重干预策略。
细胞因子生成和增殖等炎症效应功能丧失，是T细胞疗法治疗实体瘤失败的重要原因。本研究使用CRISPR/Cas9在经过临床阶段间皮素靶向CAR改造的人T细胞中敲除ZFP36。ZFP36是一种RNA结合蛋白，可调节参与T细胞炎症功能的mRNA稳定性，例如IL2和IFN-γ细胞因子mRNA。我们旨在确定敲除ZFP36能否增强抗肿瘤应答。敲除ZFP36轻度增加了非抗原依赖性活化和细胞因子应答，但在体外或NSG小鼠异种移植肿瘤模型体内均未改善总体表现。尽管敲除ZFP36不会降低CAR-T细胞功能，结果提示单独敲除ZFP36不足以提升其功能，可能需要采用多基因联合策略。
Loss of inflammatory effector function, such as cytokine production and proliferation, is a fundamental driver of failure in T cell therapies against solid tumors. Here, we used CRISPR/Cas9 to genetically disrupt ZFP36, an RNA binding protein that regulates the stability of mRNAs involved in T cell inflammatory function, such as the cytokines IL2 and IFN , in human T cells engineered with a clinical-stage mesothelin-targeting CAR to determine whether its disruption could enhance antitumor responses. ZFP36 disruption slightly increased antigen-independent activation and cytokine responses but did not enhance overall performance in vitro or in vivo in a xenograft tumor model with NSG mice. While ZFP36 disruption does not reduce the function of CAR-T cells, these results suggest that singular disruption of ZFP36 is not sufficient to improve their function and may benefit from a multiplexed approach.
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