Kojima Ryosuke, Scheller Leo, Fussenegger Martin
ETH Zurich, Department of Biosystems Science and Engineering, Basel, Switzerland.
Faculty of Life Science, University of Basel, Basel, Switzerland.
Nat Chem Biol. 2018 Jan;14(1):42-49. doi: 10.1038/nchembio.2498. Epub 2017 Nov 13.
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.
将定制的细胞接触感应输出装置设计到人类非免疫细胞中的能力，对于扩大基于细胞的癌症治疗的适用性以及避免与工程化免疫细胞相关的风险将是有用的。在这里，我们开发了一类新型的合成T细胞受体样信号转导装置，该装置在人类非免疫细胞中高效发挥作用，并在感知与靶细胞接触时特异性地触发输出分子的释放。该装置采用白细胞介素信号级联反应，其开/关切换由跨膜信号抑制蛋白从传感器细胞-靶细胞界面的生物物理分离来控制。我们进一步表明，配备该装置并驱动膜穿透剂/前药激活酶构建体表达的设计型非免疫细胞，在存在前药的情况下可以特异性杀死靶细胞，这表明其在基于细胞的、针对靶细胞特异性的酶-前药癌症治疗中具有潜在用途。我们的研究还通过扩展将细胞外信息传递到细胞的可用设计原则，为合成生物学的发展做出了贡献。
