Mechanistic Dynamic Study of Intranodal Chemokine-aided Antitumor Immune Priming

结内趋化因子辅助抗肿瘤免疫启动的机制动力学研究

基本信息

批准号：
8233500
负责人：
Alex Yee-Chen Huang
金额：
$ 32.58万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8233500
关键词：
Adjuvant Affect Animals Antigen Presentation Antigen-Presenting Cells Antigens Area Biological Assay CCL3 gene CCL4 gene CCR1 gene CD4 Positive T Lymphocytes CD8B1 gene CXCR3 gene Cell Communication Cells Communication Cross Presentation Dendritic Cells Development Disease Engineering Equilibrium Evaluation Future Gene Expression Profile Generations Goals Host resistance Immune Immune Tolerance Immune response Immune system Immunity Immunization Immunotherapeutic agent Immunotherapy In Situ Individual Infection Inflammatory Investigation Kinetics Laboratories Laser Scanning Microscopy Lymphocyte Lymphoid Maintenance Malignant Neoplasms Mediating Mediator of activation protein Memory Methods Modeling Molecular Molecular Target Occupations Organ Pathogenesis Photons Play Protocols documentation Relative (related person)Role Sensitivity and Specificity Series Site Small Inducible Cytokine A3 Specificity Surface System T cell response T memory cell T-Cell Activation T-Cell Development T-Lymphocyte Technology Testing Time Tissue-Specific Gene Expression Tissues Tumor Antigens Tumor Immunity Vaccination arm cell type chemokine chemokine receptor cytotoxic design immune activation improved in vivo insight lymph nodes migration neoplastic cell novel novel therapeutics paracrine pathogen public health relevance receptor expression research study success therapy design tumor vaccination strategy

项目摘要

DESCRIPTION (provided by applicant): The job of our immune system is to recognize foreign invaders and eliminate the threat while ignoring host tissues. Tissue microenvironment plays a critical role in orchestrating the generation of immune responses, including adaptive memory T cell immunity. Understanding how tissue microenvironment affects the balance between immune activation and unresponsiveness in vivo is crucial in defining pathogenesis of diseases such as cancer. It is also helpful in taking advantage of the exquisite sensitivity and specificity of the immune system in developing the next generation of therapeutic and vaccination strategies. Recently application of intravital 2-photon laser scanning microscopy in examining immune tissue organization and immune cellular orchestration in vivo has yielded new insights into the critical contribution of inflammatory chemokines in orchestrating efficient cell-cell cooperation among various arms of the adaptive immune response. Using animal tumor models genetically engineered to secrete inflammatory chemokines such as CCL3 and CCL4, we propose to undertake a series of studies to investigate how efficient cell-cell interaction among tumor-associated antigen presenting cells, CD4+T cells, CD8+ T cells, and tumor cells may be achieved to accomplish efficacious generation of long-term, protective anti-tumor T cell responses. We also outline an ambitious goal to directly observe, for the first time, dynamic cellular interplay in metastatic lymph nodes including direct antigen presentation by tumors and cross-presentation of tumor-associated antigens by host antigen-presenting cells during the induction of an effective immune response. This will be accomplished by utilizing the state-of-the-art 2-photon laser scanning microscopy available in our own laboratory. Success in this endeavor not only will yield new insights into how to employ inflammatory chemokines as an adjuvant in the generation of anti-tumor CD8+ memory T cells, but also will provide direct in vivo evidence for the roles which the host APC and tumors play in priming CD8+ T cells against tumor-associated antigen. A detailed understanding of the intricate cellular recruitment and communication in the tumor microenvironment will allow the development of targeted therapies designed to enhance anti-tumor immune activation. It will also provide insights into factors that will enhance targeting and recruitment of cytotoxic anti-tumor lymphocytes to tumor sites in currently existing immunotherapy protocols. PUBLIC HEALTH RELEVANCE: Ultimately, any effective cellular immunotherapy against cancer must accomplish 2 goals: 1) Finding effective adjuvant to enhance efficient generation and maintenance of long-term anti-tumor immunity; 2) Proper and rapid recruitment of relevant immune cells to sites of tumor-antigen priming, activation and effector delivery. This study seeks to investigate the cellular mechanism of enhanced anti-tumor effect by inflammatory chemokines such as CCL3 and CCL4, and the associated chemokine receptor(s). We propose to employ the state-of-the-art 2-photon laser scanning microscopy technology in order to accomplish this goal. Successful execution of this project will not only provide new insights into novel tumor immunotherapy approaches, but will also demonstrate a new in situ experimental platform to test future anti-tumor immune strategies with high cellular specificity.

描述（由申请人提供）：我们的免疫系统的工作是识别外来入侵者并消除威胁，同时忽略宿主组织。组织微环境在协调免疫反应（包括适应性记忆 T 细胞免疫）的产生中发挥着关键作用。了解组织微环境如何影响体内免疫激活和无反应之间的平衡对于确定癌症等疾病的发病机制至关重要。它还有助于利用免疫系统的精致敏感性和特异性来开发下一代治疗和疫苗接种策略。最近，应用活体 2 光子激光扫描显微镜检查体内免疫组织组织和免疫细胞编排，对炎症趋化因子在协调适应性免疫反应各分支之间有效细胞间合作的关键贡献产生了新的见解。利用基因工程改造的动物肿瘤模型来分泌炎症趋化因子（如 CCL3 和 CCL4），我们建议进行一系列研究，以研究肿瘤相关抗原呈递细胞、CD4+T 细胞、CD8+T 细胞和肿瘤细胞可以实现有效产生长期的、保护性的抗肿瘤T细胞应答。我们还概述了一个雄心勃勃的目标，即首次直接观察转移淋巴结中的动态细胞相互作用，包括肿瘤的直接抗原呈递和宿主抗原呈递细胞在诱导有效免疫过程中交叉呈递肿瘤相关抗原。回复。这将通过利用我们自己实验室中最先进的 2 光子激光扫描显微镜来实现。这项工作的成功不仅将为如何利用炎症趋化因子作为抗肿瘤 CD8+ 记忆 T 细胞的佐剂提供新的见解，而且还将为宿主 APC 和肿瘤在抗肿瘤过程中发挥的作用提供直接的体内证据。启动 CD8+ T 细胞对抗肿瘤相关抗原。对肿瘤微环境中复杂的细胞募集和通讯的详细了解将有助于开发旨在增强抗肿瘤免疫激活的靶向疗法。它还将提供对在当前现有免疫治疗方案中增强细胞毒性抗肿瘤淋巴细胞靶向和招募至肿瘤位点的因素的见解。公共健康相关性：最终，任何有效的癌症细胞免疫疗法都必须实现两个目标：1）找到有效的佐剂以增强长期抗肿瘤免疫力的有效产生和维持； 2) 正确、快速地将相关免疫细胞募集到肿瘤抗原引发、激活和效应物传递的位点。本研究旨在探讨 CCL3 和 CCL4 等炎症趋化因子以及相关趋化因子受体增强抗肿瘤作用的细胞机制。我们建议采用最先进的 2 光子激光扫描显微镜技术来实现这一目标。该项目的成功执行不仅将为新型肿瘤免疫治疗方法提供新的见解，还将展示一个新的原位实验平台来测试未来具有高细胞特异性的抗肿瘤免疫策略。