期刊
ADVANCED MATERIALS
卷 31, 期 23, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adma.201807359
关键词
adoptive T cell therapy; artificial matrix; extracellular matrix; hydrogel; immunotherapy; mechanotransduction; T cell stimulation
类别
资金
- NIH Cancer Nanotechnology Training Center at the Johns Hopkins Institute for NanoBioTechnology
- National Science Foundation Graduate Research Fellowship [DGE-1232825]
- ARCS foundation
- National Institutes of Health [5R21CA185819-02]
- IIC core: NIH SIG award [1s10OD020152-01A1, T32: 5T32CA153952-08]
- NIGMS [3T32GM007309]
- NCI [U54 CA2101732]
- Johns Hopkins University Discovery Award from the Office of the Vice Provost for Research
T cell therapies require the removal and culture of T cells ex vivo to expand several thousand-fold. However, these cells often lose the phenotype and cytotoxic functionality for mediating effective therapeutic responses. The extracellular matrix (ECM) has been used to preserve and augment cell phenotype; however, it has not been applied to cellular immunotherapies. Here, a hyaluronic acid (HA)-based hydrogel is engineered to present the two stimulatory signals required for T-cell activation-termed an artificial T-cell stimulating matrix (aTM). It is found that biophysical properties of the aTM-stimulatory ligand density, stiffness, and ECM proteins-potentiate T cell signaling and skew phenotype of both murine and human T cells. Importantly, the combination of the ECM environment and mechanically sensitive TCR signaling from the aTM results in a rapid and robust expansion of rare, antigen-specific CD8+ T cells. Adoptive transfer of these tumor-specific cells significantly suppresses tumor growth and improves animal survival compared with T cells stimulated by traditional methods. Beyond immediate immunotherapeutic applications, demonstrating the environment influences the cellular therapeutic product delineates the importance of the ECM and provides a case study of how to engineer ECM-mimetic materials for therapeutic immune stimulation in the future.
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