Mechanistic Dynamic Study of Intranodal Chemokine-aided Antitumor Immune Priming

描述(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。组织微环境在包括适应性记忆T细胞免疫在内的免疫反应的产生中起着至关重要的作用。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高度敏感性和特异性来开发下一代治疗和疫苗接种策略。最近，活体双光子激光扫描显微镜在体内检测免疫组织结构和免疫细胞编排方面的应用，使人们对炎性趋化因子在协调适应性免疫反应的各个分支之间有效的细胞-细胞协作中的关键作用有了新的认识。利用基因工程的动物肿瘤模型，如CCL3和CCL4，我们建议进行一系列研究，以探讨肿瘤相关抗原提呈细胞、CD4+T细胞、CD8+T细胞和肿瘤细胞之间的有效细胞-细胞相互作用，以实现有效地产生长期、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动态的细胞相互作用，包括肿瘤的直接抗原递呈和宿主抗原递呈细胞在诱导有效免疫反应期间对肿瘤相关抗原的交叉递呈。这将通过利用我们实验室提供的最先进的双光子激光扫描显微镜来实现。这一努力的成功不仅将为如何利用炎性趋化因子作为佐剂来产生抗肿瘤的CD8+记忆T细胞提供新的见解，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的过程中所起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治疗。它还将提供对现有免疫治疗方案中将增强靶向和向肿瘤部位招募细胞毒性抗肿瘤淋巴细胞的因素的洞察。

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.