Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-tumor Activity
| Autor: | Robert Blum, Karl-Johan Malmberg, Davide Bernareggi, Kun-Liang Guan, Huang Zhu, Chengsheng Wu, Zhipeng Meng, Zhengming Wu, Hanna Julie Hoel, Eivind Heggernes Ask, Dan S. Kaufman |
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| Rok vydání: | 2020 |
| Předmět: |
Cell
Induced Pluripotent Stem Cells Biology Article Cell therapy 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Genetics medicine Cytotoxic T cell Humans Induced pluripotent stem cell PI3K/AKT/mTOR pathway 030304 developmental biology Interleukin-15 0303 health sciences Cell Biology Cell biology Killer Cells Natural medicine.anatomical_structure Interleukin 15 Cell culture Tumor progression Molecular Medicine Cytokines 030217 neurology & neurosurgery |
| Zdroj: | Cell Stem Cell |
| ISSN: | 1875-9777 |
| Popis: | 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, CISH-/- iPSC-NK cells display improved metabolic fitness characterized by increased basal glycolysis, glycolytic capacity, maximal mitochondrial respiration, ATP-linked respiration, and spare respiration capacity mediated by mammalian target of rapamycin (mTOR) signaling that directly contributes to enhanced NK cell function. Together, these studies demonstrate that CIS plays a key role to regulate human NK cell metabolic activity and thereby modulate anti-tumor activity. |
| Databáze: | OpenAIRE |
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