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，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。

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