Engineering an Artificial T-Cell Stimulating Matrix for Immunotherapy.
Engineering an Artificial T-Cell Stimulating Matrix for Immunotherapy.
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DOI：
10.1002/adma.201807359
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发表时间：
2019-06
期刊：
影响因子：
--
通讯作者：
Schneck JP
中科院分区：
文献类型：
--
作者：
Hickey JW;Dong Y;Chung JW;Salathe SF;Pruitt HC;Li X;Chang C;Fraser AK;Bessell CA;Ewald AJ;Gerecht S;Mao HQ;Schneck JP
T细胞疗法需要去除和体外培养T细胞，使其扩增数千倍。然而，这些细胞往往失去了介导有效治疗反应的表型和细胞毒功能。细胞外基质(ECM)已被用于保存和增强细胞表型，但尚未被应用于细胞免疫治疗。在这里，一种基于透明质酸(HA)的水凝胶被设计成呈现T细胞激活所需的两种刺激信号-被称为人工T细胞刺激基质(ATM)。研究发现，ATM的生物物理特性--刺激性配体的密度、硬度和ECM蛋白--增强了T细胞的信号转导和人和鼠T细胞的偏斜表型。重要的是，ECM环境和来自ATM的机械敏感的TCR信号的结合导致了稀有的、抗原特异性的CD8+T细胞的快速而强劲的增殖。与传统方法刺激的T细胞相比，过继转移这些肿瘤特异性细胞显著抑制肿瘤生长并提高动物存活率。除了直接的免疫治疗应用外，展示环境对细胞治疗产品的影响揭示了细胞外基质的重要性，并为未来如何设计用于治疗性免疫刺激的细胞外基质模拟材料提供了一个案例研究。
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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影响因子：
15.9
作者：
Berger, Carolina;Jensen, Michael C.;Riddell, Stanley R.
通讯作者：
Riddell, Stanley R.
影响因子：
10.8
作者：
Deeg J;Axmann M;Matic J;Liapis A;Depoil D;Afrose J;Curado S;Dustin ML;Spatz JP
通讯作者：
Spatz JP
影响因子：
16.6
作者：
Chaudhuri O;Gu L;Darnell M;Klumpers D;Bencherif SA;Weaver JC;Huebsch N;Mooney DJ
通讯作者：
Mooney DJ
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
14
作者：
Hickey JW;Isser AY;Vicente FP;Warner SB;Mao HQ;Schneck JP
通讯作者：
Schneck JP