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


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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Figure 1: Evaluation of CD43ex-45int for suppressing cytokine receptor-mediated signaling pathways.
Figure 2: Development of the specific-cell-contact-sensing device.
Figure 3: The optimized specific-cell-contact-sensing system.
Figure 4: Application to target-cell-specific activatable enzyme-prodrug cancer therapy.

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We thank P. Saxena for critical comments on the manuscript, R. Vale, J. James, B. Lindner, J. Schaefer, S. Rosenberg, A. Plückthun, L. Schukur, H. Chassin, and Addgene construct suppliers (see Supplementary Information) for providing plasmids, T. Lopes and V. Jaggin for help with FACS analysis, and E. Montani, A. Ponti, and T. Horn for help with microscopy. This work was supported by the European Research Council (ERC) advanced grant (ProNet, no. 321381) and in part by the National Centre of Competence in Research (NCCR) for Molecular Systems Engineering. R.K. was supported by a postdoctoral fellowship by the Human Frontier Science Program (HFSP; LT000094/2014-L).

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R.K. and M.F. designed the project, analyzed the results, and wrote the manuscript. R.K. performed experimental work. L.S. contributed to project design and plasmid generation and edited the manuscript.

Corresponding author

Correspondence to Martin Fussenegger.

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The authors declare no competing financial interests.

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Supplementary Results, Supplementary Tables 1–2 and Supplementary Figures 1–5 (PDF 1383 kb)

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Kojima, R., Scheller, L. & Fussenegger, M. Nonimmune cells equipped with T-cell-receptor-like signaling for cancer cell ablation. Nat Chem Biol 14, 42–49 (2018).

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