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Rewiring signaling responses to soluble extracellular cues for T-cell therapies and beyond


Soluble extracellular factors are a commonly used medium of communication between a cell and its environment. The ability to program the response of cell-based therapies to such cues will help realize the promise of cell therapies as a powerful strategy to treat a variety of diseases. Here, we report on a chimeric antigen receptor (CAR) that binds the cytokine TGF-β, an immunosuppressive factor commonly upregulated at solid tumors. The TGF-β CAR rewires T-cell responses to TGF-β, converting an immunosuppressant into an immunostimulatory molecule. Additionally, TGF-β CAR-T cells can protect surrounding T cells from TGF-β–induced functional defects and differentiation into the regulatory phenotype. Using lessons learned from the in-depth case-study of the TGF-β CAR, we next establish a framework for using CARs to engineer T cells to sense synthetic and natural extracellular soluble ligands of choice and with tunable sensitivity. Our work supports that the CAR is a mechanosensitive receptor, shows that the mechanosensative synthetic Notch receptors can be employed to rewire responses to soluble ligands in mammalian cells in general, and highlights that proteins that respond to mechanical forces serve as suitable chassis for establishing biochemically modular platforms in synthetic biology.

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