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
基本信息
- 批准号:10392463
- 负责人:
- 金额:$ 47.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:3-DimensionalAdoptive TransferAnimal ModelAntibodiesAntigen PresentationAntigen-Presenting CellsAntigensAutoimmuneBindingBinding SitesBiochemicalBiomechanicsBiomimeticsBiophysicsCD4 Positive T LymphocytesCD44 geneCD8-Positive T-LymphocytesCD8B1 geneCell AdhesionCellsCellular biologyComplexCuesCytokine SignalingDataEngineeringExtracellular MatrixHumanHyaluronic AcidHydrogelsImmunotherapyIn VitroInjectableInterleukin-2Malignant NeoplasmsMediatingModelingMusOutcome StudyPathogenicityPhenotypePolymersPopulationPropertyProteinsResearch PersonnelRoleSignal TransductionT cell therapyT-Cell ActivationT-Cell DevelopmentT-LymphocyteTechnologyTestingTherapeuticTherapeutic EffectTreatment CostTreatment EfficacyWorkadaptive immunityanti-cancerbasebiophysical propertiescancer cellcancer immunotherapycell killingcytokinedensitydesigneffector T cellengineered T cellsengineering designexhaustionexperiencefightingimprovedin vivoinnovationinventionlymph node microenvironmentlymph nodesmouse modelnanofibernanoparticlenovelnovel strategiesparticleresponsesubcutaneoussynergismtherapy outcome
项目摘要
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.
项目总结
这项研究的目的是设计一种人工T细胞刺激基质(ATM),它呈现抗原特异性
和细胞特异的生化和生物物理线索来控制T细胞的表型和改善其功能
仿生背景,捕捉淋巴(LN)的关键生化和生物物理特征。LN提供了
关键微环境,协调抗原特异信号的呈现格式和动态
精确和可控的方式,导致T细胞的激活、扩增和成熟。当前可用的T细胞
然而,在携带抗原呈递复合体和共刺激线索的同时刺激基质,缺乏
LN中T细胞刺激微环境所固有的足够支持线索。我们将设计和
描述集成了三个关键T细胞刺激信号的ATM的特征: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)分子和可调生物物理
由抗原提呈细胞(APC)和LN的特性启发而来的特性。我们将检验这一假设
在T细胞刺激期间在这样的仿生环境中共同呈现APC信号提示将导致功能性
具有受控表型和效力的T细胞。以及揭示所有信号信号如何协同作用的机制
活化和极化T细胞。在具体目标1中,我们将确定ATM的关键矩阵属性
透明质酸水凝胶和透明质酸纳米纤维复合材料制备的ATM对CD8+T细胞的激活作用
矩阵。在具体目标2中,我们将定义影响最佳信令提示及其呈现配置
在ATM上的CD4+T细胞的激活和极化;并展示了ATM刺激的和
过继转移的抗原特异性CD4+T细胞。在特定的目标3中,我们将使用ATM微粒来协同刺激
CD_8~+和CD_4~+T细胞及其联合治疗的疗效
一种肿瘤免疫治疗的小鼠模型。如果成功,这项研究将产生第一套工程化ATM
提供强大的抗原特异性CD8+和CD4+T细胞的刺激,承诺改善治疗结果;
进一步丰富了我们对刺激、极化等信号传递线索的设计原理和机制的理解
和T细胞的激活。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Hai-Quan Mao其他文献
Hai-Quan Mao的其他文献
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{{ truncateString('Hai-Quan Mao', 18)}}的其他基金
A nanofiber-hydrogel composite plug for perianal fistula repair
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- 资助金额:
$ 47.94万 - 项目类别:
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
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