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.

项目总结/摘要 具有活化和扩增的T或CAR T细胞的免疫细胞疗法（ACT）可用于治疗感染或免疫缺陷。 肿瘤和ACT与T或CAR T调节细胞的临床试验，以控制自身免疫和同种异体移植 排斥反应许多但不是所有患者都受益。ACT的成功取决于T细胞归巢到相关组织 网站.正常的循环T效应记忆或T调节细胞可以响应于它们的同源物进入组织。 在TCR触发的过程中，抗原展示在局部微血管EC的表面上， 由共刺激调节。我们假设人内皮细胞（EC）的抗原呈递 将募集过继转移的体外扩增的T或CAR T效应细胞和调节细胞，以特异性地 在由特定EC共刺激因子调节的过程中，外周组织部位。具体目标1： 我们在流动室中使用内皮细胞单层开发的体外模型中验证了这一假设 以模拟体内条件。我们将扩大我们的体外系统，包括检查TCR的影响， 诱导的跨内皮迁移（TEM）在单细胞水平上对T细胞的影响。在CAR T细胞的情况下， 我们将确定最重要的共刺激分子受体分子基序，以纳入CAR， 最佳TEM我们还将确定人类EC是否具有交叉呈现或“变装”的能力， 允许EC呈递抗原的抗原影响癌症免疫治疗。最后，我们将使用一个模型 我们开发了用于研究过继转移的人类T细胞对扩张微血管的反应， 从人类EC组装，允许对人类EC可以提供的信号进行遗传操作。在aim 2中 我们将使用T和CAR T调节细胞进行类似的实验。圆满完成这些目标 将为扩大可能受益于ACT的患者范围提供重要信息。