Mechanisms and consequences of antigen-dependent T cell homing for adoptive immunotherapies

过继免疫疗法中抗原依赖性 T 细胞归巢的机制和后果

• 批准号: 10654215
• 负责人: Thomas David Manes
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654215
• 关键词: Adoptive Cell Transfers; Adoptive Immunotherapy; Adoptive Transfer; Affect; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autoimmunity; Blood Vessels; CD8B1 gene; Cell Adhesion Molecules; Cell Line; Cell surface; Cells; Clinical Trials; Cross Presentation; Cytoplasm; Disease; Dual-role transvestism; Endothelial Cells; Endothelium; Gene Transfer; Homing; Human; Immunology; Implant; In Vitro; Infection; Infusion procedures; Interleukin-2; Knowledge; Laboratories; Ligands; Mediating; Medical; Memory; Modeling; Molecular; Mus; Organelles; Patients; Pattern; Peptide/MHC Complex; Peripheral; Phenotype; Play; Population; Process; Production; Regulatory T-Lymphocyte; Role; Signal Induction; Signal Transduction; Site; Surface; T cell differentiation; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Tissues; Treatment Efficacy; Tubular formation; Vascular Endothelial Cell; Viral Cancer; Virus Diseases; allograft rejection; antigen-specific T cells; autoinflammatory diseases; cancer immunotherapy; chemokine; chimeric antigen receptor; chimeric antigen receptor T cells; cytokine; effector T cell; experimental study; genetic manipulation; human migration; immunodeficient mouse model; in vitro Model; in vivo; in vivo Model; migration; monolayer; receptor; recruit; response; species difference; success; tumor

Project Summary/Abstract Adoptive cell therapy (ACT) with activated and expanded T or CAR T cells may be used to treat infections or tumors and ACT with T or CAR T regulatory cells are in clinical trials to control autoimmunity and allograft rejection. Many but not all patients benefit. The success of ACT depends upon T cell homing to relevant tissue sites. Normal circulating T effector memory or T regulatory cells can enter a tissue in response to their cognate antigen being displayed on the surface of the local microvascular ECs in a process triggered by TCR and modulated by costimulation. We hypothesize that antigen presentation by human endothelial cells (ECs) will recruit adoptively transferred in vitro expanded T or CAR T effector and regulatory cells to specific peripheral tissue sites in a process modulated by specific EC co-stimulators. In specific aim 1, we will test this hypothesis in vitro in models we have developed using endothelial cell monolayers in flow chambers to model in vivo conditions. We will expand our in vitro assys to include an examination of the effects that TCR- induced transendothelial migration (TEM) has on the T cells at the single cell level. In the case of CAR T cells, we will determine the most important costimulator receptor molecule motifs to be incorporated into the CAR for optimal TEM. We will also determine if human ECs have the capacity to cross-present or be “cross-dressed” by antigens allowing EC presentation of antigen to influence cancer immunotherapy. Finally, we will use a model we developed for studying adoptively transferred human T cell responses to synthestic microvessels assembled from human ECs, allowing genetic manipulation of the signals human ECs can provide. In aim 2 we will conduct similar experiments using T and CAR T regulatory cells. Successful completion of these aims will provide important information for extending the range of patients who may benefit from ACT.

项目摘要/摘要 具有活化和扩展的T或CAR T细胞的收养细胞疗法（ACT）可用于治疗感染或 肿瘤和用T或CAR T调节细胞起作用，正在临床试验中，以控制自身免疫性和同种异体移植 拒绝。许多但并非所有患者都受益。 ACT的成功取决于T细胞的归位为相关组织 站点。正常的循环T效应记忆或T调节细胞可以响应其同源而进入组织 在TCR和 通过共刺激调节。我们假设人类内皮细胞（EC）的抗原表现 将在体外扩展的T或CAR T效应子和调节细胞中适当转移到特定的 在特定EC共刺激剂调节的过程中，外围组织位点。在特定目标1中，我们将 在模型中在体外检验该假设，我们使用流室中的内皮细胞单层开发 模拟体内条件。我们将扩展我们的体外化合物，包括检查TCR-的影响 诱导的跨内皮迁移（TEM）在单细胞水平的T细胞上具有。对于汽车T细胞， 我们将确定要合并到汽车中的最重要的costimulator接收器分子图案 最佳TEM。我们还将确定人类EC是否有能力通过 抗原允许EC呈递抗原会影响癌症免疫疗法。最后，我们将使用模型 我们开发了用于研究适当转移的人类T细胞对合成微血管的反应 从人类EC组装，允许对人类EC的信号进行遗传操纵。在目标2中 我们将使用T和CAR T调节细胞进行类似的实验。这些目标成功完成 将提供重要信息，以扩大可能从ACT中受益的患者的范围​​。