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.

项目摘要 这项研究的目的是设计一个呈现抗原特异性的人造T细胞刺激基质（ATM） 以及细胞特异性的生化和生物物理提示，以控制表型并改善A中T细胞的功能分布 捕获淋巴结（LN）的关键生化和生物物理特征的仿生环境。 LN提供 策划抗原特异性信号的演示形式和动力学的关键微环境 精确和受控的方式，导致T细胞激活，膨胀和成熟。目前可用的T单元 但是，携带抗原呈递复合物并共同刺激提示的刺激矩阵缺乏 足够的支持T细胞固有的线索刺激LN中的微环境。我们将设计和 表征整合三个键T细胞刺激信号的ATM：抗原特异性（信号1），共刺激性 （信号2）和细胞因子（信号3），以及细胞外基质（ECM）分子和可调生物物理 受抗原呈递细胞（APC）和LN的性质启发的特性。我们将检验假设 在T细胞刺激过程中，在这种仿生环境中共同呈现APC信号提示将导致功能 具有受控表型特征和效力的T细胞。和机制揭示了所有信号提示如何协同作用 活性和极化T细胞。在特定目标1中，我们将确定介导稳定性的ATM的键矩阵属性 CD8+ T细胞使用由透明质酸（HA）水凝胶和HA纳米纤维复合材料（NHC）制备的ATM激活 矩阵。在特定目标2中，我们将定义最佳信号提示及其影响的表现配置 ATM上的CD4+ T细胞激活和极化；并证明ATM刺激的持久性和功能 采用转移的抗原特异性CD4+ T细胞。在特定的目标3中，我们将使用ATM微粒共同刺激 CD8+和CD4+ T细胞，并评估与CD4+和CD8+ T细胞组合治疗的治疗益处 癌症免疫疗法小鼠模型。如果成功，这项研究将导致第一组工程的ATM 提供有力的抗原特异性CD8+和CD4+ T细胞的强大刺激，这些CD4+ T细胞有望改善治疗结果； 并进一步丰富了我们对刺激，极化，信号线索的设计原理的理解和机制 和T细胞的激活。