期刊
NATURE CHEMICAL BIOLOGY
卷 14, 期 1, 页码 42-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2498
关键词
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资金
- European Research Council (ERC) advanced grant (ProNet) [321381]
- National Centre of Competence in Research (NCCR) for Molecular Systems Engineering
- Human Frontier Science Program (HFSP) [LT000094/2014-L]
The ability to engineer custom cell-contact-sensing output devices into human nonimmune cells would be useful for extending the applicability of cell-based cancer therapies and for avoiding risks associated with engineered immune cells. Here we have developed a new class of synthetic T-cell receptor-like signal-transduction device that functions efficiently in human nonimmune cells and triggers release of output molecules specifically upon sensing contact with a target cell. This device employs an interleukin signaling cascade, whose OFF/ON switching is controlled by biophysical segregation of a transmembrane signal-inhibitory protein from the sensor cell-target cell interface. We further show that designer nonimmune cells equipped with this device driving expression of a membrane-penetrator/prodrug-activating enzyme construct could specifically kill target cells in the presence of the prodrug, indicating its potential usefulness for target-cell-specific, cell-based enzyme-prodrug cancer therapy. Our study also contributes to the advancement of synthetic biology by extending available design principles to transmit extracellular information to cells.
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