CISH敲除促进重编程澳门永利网站NK细胞肿瘤杀伤活力2020-06-15 16:05

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本期文章:《细胞—干细胞》:Online/在线发表

近日,美国加州大学圣迭戈分校Dan S. Kaufman小组发现,敲除人类iPSC来源的NK细胞CISH能够发生代谢重编程,澳门永利官网,澳门永利网址,从而促进体内持久性并增强抗肿瘤活性。相关论文于2020年6月11日在线发表在《细胞—干细胞》杂志上。

研究人员使用诱导型多能干细胞来源的自然杀伤细胞(iPSC-NK细胞)平台开发人类CISH基因敲除(CISH-/-)NK细胞。CISH-/-iPSC-NK细胞表现出增加的白介素15(IL-15)介导的JAK-STAT信号活性。因此,澳门永利网址,当维持在低细胞因子浓度时,CISH-/-iPSC-NK细胞表现出增强的扩增能力,并且对多种肿瘤细胞系的细胞毒性增强。CISH-/-iPSC-NK细胞在白血病异种移植模型中显示出体内持久性的显著提高并且对肿瘤进展的抑制。

 

从机理上讲,CISH-/-iPSC-NK细胞表现出增强的代谢适应性,其特征是基础糖酵解、糖酵解能力、最大线粒体呼吸、ATP关联呼吸和备用呼吸能力的增强,这些由哺乳动物雷帕霉素靶标(mTOR)信号所介导,直接有助于增强NK细胞的功能。

 

总之,这些研究表明,CIS在调节人类NK细胞的代谢活性从而调节抗肿瘤活性方面起着关键作用。

 

据悉,细胞因子诱导型含SH2蛋白(CIS;由CISH基因编码)是NK细胞中IL-15信号传导的关键负调控因子。

 

附:英文原文

Title: Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-tumor Activity

Author: Huang Zhu, Robert H. Blum, Davide Bernareggi, Eivind Heggernes Ask, Zhengming Wu, Hanna Julie Hoel, Zhipeng Meng, Chengsheng Wu, Kun-Liang Guan, Karl-Johan Malmberg, Dan S. Kaufman

Issue&Volume: 2020-06-11

Abstract: Cytokine-inducible SH2-containing protein (CIS; encoded by the gene CISH) is a key negative regulator of interleukin-15 (IL-15) signaling in natural killer(NK) cells. Here, we develop human CISH-knockout (CISH/) NK cells using an induced pluripotent stem cell-derived NK cell (iPSC-NK cell) platform.CISH/ iPSC-NK cells demonstrate increased IL-15-mediated JAK-STAT signaling activity. Consequently,CISH/ iPSC-NK cells exhibit improved expansion and increased cytotoxic activity againstmultiple tumor cell lines when maintained at low cytokine concentrations. CISH/ iPSC-NK cells display significantly increased in vivo persistence and inhibition of tumor progression in a leukemia xenograft model. Mechanistically,CISH/ iPSC-NK cells display improved metabolic fitness characterized by increased basalglycolysis, glycolytic capacity, maximal mitochondrial respiration, ATP-linked respiration,and spare respiration capacity mediated by mammalian target of rapamycin (mTOR) signalingthat directly contributes to enhanced NK cell function. Together, these studies demonstratethat CIS plays a key role to regulate human NK cell metabolic activity and therebymodulate anti-tumor activity.

DOI: 10.1016/j.stem.2020.05.008

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30206-X

期刊信息

Cell Stem Cell:《细胞—干细胞》,创刊于2007年。隶属于细胞出版社,最新IF:21.464
官方网址:https://www.cell.com/cell-stem-cell/home
投稿链接:https://www.editorialmanager.com/cell-stem-cell/default.aspx


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