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: 8623746
• 负责人: Alex Yee-Chen Huang
• 金额: $ 5.62万
• 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/8623746
• 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; Genetic Engineering; 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; tumor microenvironment; 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.

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。我们建议利用基因工程分泌CCL3和CCL4等炎症趋化因子的动物肿瘤模型，进行一系列研究，以研究如何在肿瘤相关抗原呈递细胞、CD4+T细胞、CD8+T细胞和肿瘤细胞之间实现有效的细胞-细胞相互作用，从而有效地产生长期的、保护性的抗肿瘤T细胞反应。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反应期间交叉呈递肿瘤相关抗原。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 细胞生成的佐剂提供新的见解，而且还将为宿主 APC 和肿瘤在启动 CD8+ T 细胞对抗肿瘤相关抗原方面所发挥的作用提供直接的体内证据。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。