Adv Mater. 2019 Apr 10:e1807359. doi: 10.1002/adma.201807359. [Epub ahead of print]

Engineering an Artificial T-Cell Stimulating Matrix for Immunotherapy.

Hickey JW^1,2,3,4,5, Dong Y⁶, Chung JW⁷, Salathe SF⁸, Pruitt HC^5,7, Li X^4,9, Chang C^1,4, Fraser AK^1,10, Bessell CA⁶, Ewald AJ^1,10,11, Gerecht S^1,5,7,9,12, Mao HQ^1,4,5,9, Schneck JP^2,3,13.

Abstract

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.