Engineering an Artificial T‐Cell Stimulating Matrix for Immunotherapy. Issue 23 (10th April 2019)

• Record Type: Journal Article
• Authors: Hickey, John W.; Dong, Yi; Chung, Jae Wook; Salathe, Sebastian F.; Pruitt, Hawley C.; Li, Xiaowei; Chang, Calvin; Fraser, Andrew K.; Bessell, Catherine A.; Ewald, Andrew J.; Gerecht, Sharon; Mao, Hai‐Quan; Schneck, Jonathan P.
• Is Part Of: Advanced materials. Volume 31:Issue 23(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-04-10
• Subjects: adoptive T cell therapy -- artificial matrix -- extracellular matrix -- hydrogel -- immunotherapy -- mechanotransduction -- T cell stimulation; Materials -- Periodicals; Chemical vapor deposition -- Periodicals; 620.11
• DOI: 10.1002/adma.201807359
• Languages: English
• ISSNs: 0935-9648

Abstract

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. Abstract : Significant improvements to cellular immunotherapy for cancer is achieved through engineering a novel T‐cell stimulating biomaterial hydrogel. Particularly interesting, the stiffness of the hydrogel drastically impacts mechanically sensitive T cell stimulation. Similarly, the hydrogel material, hyaluronic acid, contributes additional beneficial signaling to maintain a functional phenotype of stimulated T cells, demonstrating the importance of the environment on immune cell therapies.