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Nat Chem Biol. 2017 Nov 13. doi: 10.1038/nchembio.2498. [Epub ahead of print]

Nonimmune cells equipped with T-cell-receptor-like signaling for cancer cell ablation.

Author information

1
ETH Zurich, Department of Biosystems Science and Engineering, Basel, Switzerland.
2
Faculty of Life Science, University of Basel, Basel, Switzerland.

Abstract

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.

PMID:
29131143
DOI:
10.1038/nchembio.2498
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