Biomimetic Matrix for Ex Vivo and In Vivo Activation of T Cells

用于 T 细胞离体和体内激活的仿生基质

• 批准号: 10392463
• 负责人: Hai-Quan Mao
• 金额: $ 47.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392463
• 关键词: 3-Dimensional; Adoptive Transfer; Animal Model; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autoimmune; Binding; Binding Sites; Biochemical; Biomechanics; Biomimetics; Biophysics; CD4 Positive T Lymphocytes; CD44 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Adhesion; Cells; Cellular biology; Complex; Cues; Cytokine Signaling; Data; Engineering; Extracellular Matrix; Human; Hyaluronic Acid; Hydrogels; Immunotherapy; In Vitro; Injectable; Interleukin-2; Malignant Neoplasms; Mediating; Modeling; Mus; Outcome Study; Pathogenicity; Phenotype; Polymers; Population; Property; Proteins; Research Personnel; Role; Signal Transduction; T cell therapy; T-Cell Activation; T-Cell Development; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Effect; Treatment Cost; Treatment Efficacy; Work; adaptive immunity; anti-cancer; base; biophysical properties; cancer cell; cancer immunotherapy; cell killing; cytokine; density; design; effector T cell; engineered T cells; engineering design; exhaustion; experience; fighting; improved; in vivo; innovation; invention; lymph node microenvironment; lymph nodes; mouse model; nanofiber; nanoparticle; novel; novel strategies; particle; response; subcutaneous; synergism; therapy outcome

PROJECT SUMMARY The objective of this study is to engineer an artificial T cell-stimulating matrix (aTM) that presents antigen-specific and cell-specific biochemical and biophysical cues to control phenotype and improve functional profiles of T cells in a biomimetic context that captures key biochemical and biophysical features of the lymph node (LN). LN provides the critical microenvironment that orchestrates the presentation format and dynamics of the antigen-specific signals in a precise and controlled manner that leads to T cell activation, expansion, and maturation. Currently available T cell stimulating matrices while carrying the antigen-presentation complexes and co-stimulating cues, however, lacks adequate supporting cues inherent to the T cell stimulating microenvironment in the LN. We will design and characterize an aTM that integrates the three key T-cell stimulating signals: antigen-specific (Signal 1), co-stimulatory (Signal 2), and cytokines (Signal 3), together with extracellular matrix (ECM) molecules and tunable biophysical properties inspired by the properties of both antigen-presenting cells (APCs) and the LN. We will test the hypothesis that co-presenting the APC signal cues in such a biomimetic context during T cell stimulation will result in functional T cells with controlled phenotypic profiles and potency. and mechanism revealing how all signaling cues synergize to active and polarize T cells. In Specific Aim 1, we will determine key matrix properties of the aTM that mediate robust CD8+ T cell activation using aTMs prepared from hyaluronic acid (HA) hydrogel and HA-nanofiber composite (NHC) matrix. In Specific Aim 2, we will define optimal signaling cues and their presentation configuration that influence CD4+ T cell activation and polarization on aTM; and demonstrate persistence and functions of aTM-stimulated and adoptively transferred antigen-specific CD4+ T cells. In Specific Aim 3, we will use aTM microparticles to co-stimulate CD8+ and CD4+ T cells and evaluate therapeutic benefits of a combination treatment with CD4+ and CD8+ T cells in a cancer immunotherapy mouse model. If successful, this study will result in the first set of engineered aTM that delivers robust stimulation of antigen-specific CD8+ and CD4+ T cells that promise improved therapeutic outcomes; and further enrich our understandings of design principles and mechanism of signaling cues in stimulation, polarization, and activation of T cells.

项目概要 本研究的目的是设计一种能够呈现抗原特异性的人工 T 细胞刺激基质 (aTM) 以及细胞特异性生化和生物物理线索，以控制表型并改善 T 细胞的功能特征 仿生环境捕获淋巴结 (LN) 的关键生化和生物物理特征。 LN 提供 关键的微环境，协调抗原特异性信号的呈现格式和动态 精确且受控的方式导致 T 细胞激活、扩增和成熟。目前可用的T细胞 然而，在携带抗原呈递复合物和共刺激线索的同时刺激基质，缺乏 LN 中 T 细胞刺激微环境固有的足够的支持线索。我们将设计和 表征集成了三个关键 T 细胞刺激信号的 aTM：抗原特异性（信号 1）、共刺激 （信号 2）和细胞因子（信号 3），以及细胞外基质 (ECM) 分子和可调节的生物物理学 其特性受到抗原呈递细胞 (APC) 和 LN 特性的启发。我们将检验假设 在 T 细胞刺激期间，在这种仿生环境中共同呈现 APC 信号线索将导致功能性 具有受控表型特征和效力的 T 细胞。以及揭示所有信号线索如何协同作用的机制 激活并极化 T 细胞。在具体目标 1 中，我们将确定调节鲁棒性的 aTM 的关键矩阵属性 使用透明质酸 (HA) 水凝胶和 HA-纳米纤维复合材料 (NHC) 制备的 aTM 激活 CD8+ T 细胞 矩阵。在具体目标 2 中，我们将定义最佳信号提示及其影响的呈现配置 aTM 上 CD4+ T 细胞的激活和极化；并展示aTM刺激和的持久性和功能 过继转移的抗原特异性 CD4+ T 细胞。在Specific Aim 3中，我们将使用aTM微粒来共同刺激 CD8+ 和 CD4+ T 细胞，并评估 CD4+ 和 CD8+ T 细胞联合治疗的治疗效果 癌症免疫治疗小鼠模型。如果成功，这项研究将产生第一套工程 aTM 强烈刺激抗原特异性 CD8+ 和 CD4+ T 细胞，有望改善治疗效果； 进一步丰富我们对刺激、极化、 和 T 细胞的激活。