Engineering an Artificial T-Cell Stimulating Matrix for Immunotherapy

Adv Mater. 2019 Jun;31(23):e1807359. doi: 10.1002/adma.201807359. Epub 2019 Apr 10.


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.

Keywords: T cell stimulation; adoptive T cell therapy; artificial matrix; extracellular matrix; hydrogel; immunotherapy; mechanotransduction.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Artificial Cells / cytology*
  • Artificial Cells / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Engineering / methods*
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Cytokines / metabolism
  • Extracellular Matrix / chemistry
  • Humans
  • Hyaluronic Acid / chemistry
  • Hydrogels
  • Immunotherapy / methods*
  • Ligands
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / therapy
  • Mice
  • Mice, Transgenic
  • Neoplasm Transplantation
  • Receptors, Antigen, T-Cell / physiology
  • Signal Transduction
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism


  • Cytokines
  • Hydrogels
  • Ligands
  • Receptors, Antigen, T-Cell
  • Hyaluronic Acid