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在CLL细胞中的p66Shc缺乏会增强PD-L1的表达,并抑制免疫突触的形成

Ludovica Lopresti¹, Nagaja Capitani¹, Vanessa Tatangelo¹

¹Department of Life Sciences, University of Siena, Siena, Italy.

Frontiers in cell and developmental biology

|February 23, 2024

概括

慢性淋巴细胞白血病 (CLL) 细胞通过过度表达PD-L1,抑制T细胞来逃避免疫监测. 这项研究表明,CLL细胞中的p66Shc缺乏会损害活性氧物种 (ROS) 的产生,导致PD-L1增加,并阻碍抗瘤免疫力.

科学领域:

免疫学免疫学免疫学
在瘤学瘤学.
细胞生物学细胞生物学

背景情况:

慢性淋巴细胞白血病 (CLL) 细胞通过抑制淋巴体器官内的T淋巴细胞来逃避免疫监测.
在CLL细胞上过度表达PD-L1,通过干扰免疫突触 (IS) 形成来抑制T细胞介导的抗瘤活性.
对于CLL中PD-L1过度表达的分子基础尚不清楚,尽管NF-κB调节和p66Shc缺乏症有关.

研究的目的:

调查p66Shc缺乏,活性氧物种 (ROS) 生产和CLL中PD-L1过度表达之间的机制联系.
阐明这些分子变化如何在CLL微环境中促进T细胞抑制.

主要方法:

通过流细胞计和qRT-PCR对62名CLL患者和43名健康捐赠者的B细胞中PD-L1和p66Shc表达的量化.
使用流细胞计和共聚焦显微镜评估免疫突触 (IS) 架构和信号.
评估CD8+T细胞杀死活性和p66Shc在CLL细胞和MEC-1细胞系中的复合实验.

主要成果:

在CLL细胞中减少的p66Shc表达与增加的PD-L1水平相反相关,损害了T淋巴细胞的IS形成.
在CLL细胞中恢复p66Shc功能增强了细胞内ROS和降低了PD-L1表达.
外源ROS (H2O2) 在CLL细胞中使PD-L1表达正常化并恢复了IS形成.

结论:

在CLL细胞中p66Shc缺乏导致ROS耗尽,因此上调PD-L1表达.
这种机制有助于抑制免疫抑制性CLL利基中的T细胞介导的抗瘤功能.
准p66Shc-ROS-PD-L1轴可能提供针对CLL的治疗策略.

关键词:

在 CLL CLL 中.在PD-L1中.这就是ROSOS ROS.免疫检查点是一个检查点.免疫突触的突触发生.p66Shccc 在线阅读

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