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

• 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
• 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

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应答（包括适应性记忆T细胞免疫）的产生中起关键作用。了解组织微环境如何影响体内免疫激活和无反应性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灵敏度和特异性来开发下一代治疗和疫苗接种策略。最近应用活体双光子激光扫描显微镜检查免疫组织组织和免疫细胞编排在体内产生了新的见解炎症趋化因子在编排有效的细胞-细胞之间的合作，适应性免疫反应的各个武器的关键贡献。使用经基因工程改造以分泌炎性趋化因子（如CCL 3和CCL 4）的动物肿瘤模型，我们建议进行一系列研究以研究肿瘤相关抗原呈递细胞、CD 4 +T细胞、CD 8 + T细胞和肿瘤细胞之间的有效细胞-细胞相互作用如何实现以实现长期保护性抗肿瘤T细胞应答的有效产生。我们还概述了一个雄心勃勃的目标，即首次直接观察转移性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应答期间对肿瘤相关抗原的交叉呈递。这将是通过利用国家的最先进的2-光子激光扫描显微镜在我们自己的实验室。这一奋进的成功不仅将产生新的见解，如何采用炎症趋化因子作为佐剂在抗肿瘤CD 8+记忆T细胞的产生，但也将提供直接的体内证据的作用，宿主APC和肿瘤在启动CD 8 + T细胞对肿瘤相关抗原。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治疗。它还将提供对在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募集至肿瘤部位的因素的见解。 公共卫生相关性：最终，针对癌症的任何有效的细胞免疫疗法必须实现2个目标：1）找到有效的佐剂以增强长期抗肿瘤免疫的有效产生和维持; 2）将相关免疫细胞适当且快速地募集到肿瘤抗原引发、活化和效应子递送的位点。本研究旨在探讨炎性趋化因子如CCL 3和CCL 4及其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双光子激光扫描显微镜技术，以实现这一目标。该项目的成功实施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，以测试未来具有高细胞特异性的抗肿瘤免疫策略。