Synthetic Viscoelastic Activating Cells for T Cell Engineering and Cancer Therapy
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ABSTRACT:
PROVIDER: PRJNA1013816 | ENA |
REPOSITORIES: ENA
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Project description:Immunotherapy shows promise in cancer treatment, but its effectiveness and durability remain limited, and improved technology for engineering immune cells is necessary. Here we develop a scalable platform that creates synthetic viscoelastic activating cells (SynVACs) with programmable mechanical and chemical properties. We demonstrate that the viscoelastic nature of SynVACs significantly impacts T cell functionality. Compared to rigid or elastic microspheres, SynVACs greatly enhance human T cell expansion, achieving approximately 90% chimeric antigen receptor (CAR) transduction efficiency. Additionally, SynVACs promote CD8+ T cell generation while suppressing regulatory T cell formation, resulting in enhanced tumor killing capability. Notably, expanding CAR-T cells with SynVACs leads to a ten-fold increase in T memory stem cells (TMSCs). These engineered CAR-T cells exhibit superior efficacy in eliminating tumor cells in a human lymphoma and ovarian xenograft mouse model, persisting in vivo for longer time period. These findings underscore the crucial role of mechanical signals in T cell engineering and highlight SynVACs' potential in CAR-T therapy and imunoengineering applications.
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Project description:Synthetic Notch (synNotch) receptors are modular synthetic components that are genetically engineered into mammalian cells to detect signals presented by neighboring cells and respond by activating prescribed transcriptional programs. To date, synNotch has been used to program therapeutic cells and pattern morphogenesis in multicellular systems. However, cell-presented ligands have limited versatility for applications that require spatial precision, such as tissue engineering. To address this, we developed a suite of materials to activate synNotch receptors and serve as generalizable platforms for generating user-defined material-to-cell signaling pathways. First, we demonstrate that synNotch ligands, such as GFP, can be conjugated to cell- generated ECM proteins via genetic engineering of fibronectin produced by fibroblasts. We then used enzymatic or click chemistry to covalently link synNotch ligands to gelatin polymers to activate synNotch receptors in cells grown on or within a hydrogel. To achieve microscale control over synNotch activation in cell monolayers, we microcontact printed synNotch ligands onto a surface. We also patterned tissues comprising cells with up to three distinct phenotypes by engineering cells with two distinct synthetic pathways and culturing them on surfaces microfluidically patterned with two synNotch ligands. We showcase this technology by co-transdifferentiating fibroblasts into skeletal muscle or endothelial cell precursors in user-defined spatial patterns towards the engineering of muscle tissue with prescribed vascular networks. Collectively, this suite of approaches extends the synNotch toolkit and provides novel avenues for spatially controlling cellular phenotypes in mammalian multicellular systems, with many broad applications in developmental biology, synthetic morphogenesis, human tissue modeling, and regenerative medicine.
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