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.

项目概要/摘要 使用活化和扩增的 T 或 CAR T 细胞的过继细胞疗法 (ACT) 可用于治疗感染或 肿瘤和 T 或 CAR T 调节细胞的 ACT 正在进行控制自身免疫和同种异体移植的临床试验 许多但不是所有患者都能受益，ACT 的成功取决于 T 细胞归巢到相关组织。 正常循环 T 效应记忆或 T 调节细胞可以响应其同源而进入组织。 抗原在 TCR 触发的过程中展示在局部微血管 EC 的表面上， 我们勇敢地面对人类内皮细胞（EC）的抗原呈递。 将招募主动转移的体外扩增 T 或 CAR T 效应细胞和调节细胞至特定 在特定目标 1 中，我们将研究由特定 EC 共刺激器调节的过程中的外周组织部位。 在我们使用流动室中的内皮细胞单层开发的模型中体外测试这一假设 我们将扩展我们的体外试验，以包括对 TCR- 的影响进行检查。 诱导跨内皮迁移 (TEM) 在单细胞水平上作用于 T 细胞。 我们将确定要纳入 CAR 的最重要的共刺激受体分子基序 我们还将确定人类 EC 是否具有交叉呈现或“异装”的能力。 抗原允许 EC 呈递抗原来影响癌症免疫治疗。 我们开发用于研究过继转移的人类 T 细胞对合成微血管的反应 由人类 EC 组装而成，允许对人类 EC 可以提供的信号进行基因操作，实现目标 2。 我们将使用 T 和 CAR T 调节细胞进行类似的实验，成功完成这些目标。 将为扩大可能受益于 ACT 的患者范围提供重要信息。