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

Cell Stem Cell. 2020-06-01; 
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
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Synthetic sgRNA and crRNA Service … CAAGGGCTGCATGACTGGCT, crRNA-2#: TGCTGGGGCCTTCCTCGAGG; DNA templates for gRNA were synthesized and cloned into pGS- gRNA (GenScript, Inc). pSpCas9 (GenScript PX165, 2 µg), pGS-gRNA-1# (1 µg) and gRNA-2# (1 µg) were co … Get A Quote

摘要

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 against multiple 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, CIS... More

关键词

CISH, IL-15, JAK-STAT, acute myelogenous leukemia, cell therapy, iPSCs, immunotherapy, mTOR, metabolic reprograming, natural killer cells