Modeling the Role of Lymph Node Metastases in Tumor-Mediated Immunosuppression

摘要/总结-总体 远处转移是癌症相关死亡的主要原因。为了在远处的组织中定居，癌细胞必须 在逃避免疫系统清除的同时迁移。有证据表明，上岗培训的关键步骤 免疫耐受过程发生在转移级联的早期，位于区域淋巴结。然而，在这方面， 肿瘤和免疫细胞之间相互作用的本质仍然知之甚少，特别是对于 发生在淋巴结内。尽管淋巴结实际上通常被评估为癌症 患者确定疾病阶段和治疗计划，他们在转移性肿瘤的背景下进行了充分研究。 进展为了填补这一科学知识空白，我们建议建立一个研究中心，重点研究淋巴的作用。 肿瘤介导的免疫抑制中的淋巴结转移。我们假设淋巴结转移 构成了癌症进展的转移级联中的重要的第一步。根据我们初步的 研究结果，我们推测这种转移局部作用于淋巴结内的适应性免疫系统， 开始诱导肿瘤的全身耐受。我们将探讨，比较和测试这一假设在两个 恶性肿瘤：（i）黑色素瘤和（ii）头颈部鳞状细胞癌。我们组建了一个 一个多学科小组，其协调工作将涉及基因组和单细胞原位应用 临床前和人体样本的成像技术，以探索证据和机制， 在淋巴结中诱导免疫抑制。我们提出了三个相互关联的研究项目 将我们的科学主题集中在不同的平台上：小鼠模型（项目1），高维原位 成像（项目2）和综合计算分析（项目3）。这三个项目都将利用一个共享的 专用于采集患者样本以及相关临床注释和数据的资源核心 生物样本和数据管理核心。这些努力将产生高度多路复用，多尺度 数据集，将通过新的生物计算方法进行分析，以重建细胞内和 细胞间分子相互作用网络，以确定，然后功能验证，关键介质， 肿瘤免疫抑制我们的最终目标是促进我们对系统性 淋巴结转移的后果，并确定癌症免疫治疗的新治疗方法。 我们的研究中心也致力于促进我们的早期研究人员作为下一代的思想 癌症系统生物学的领导者。我们的外展核心将确保我们的研究中心的科学和 在应用癌症系统生物学原理进行肿瘤研究方面的方法学进展， 免疫相互作用在癌症研究和更广泛的社区中得到充分传播。

ABSTRACT/SUMMARY – Overall Distant metastasis is the primary cause of cancer-related death. To colonize distant tissues, cancer cells must migrate while evading elimination by the immune system. Evidence suggests that key steps in the induction process of immune tolerance occur early in the metastatic cascade, located at regional lymph nodes. However, the nature of the interactions between tumors and immune cells remains poorly understood, particularly for those occurring within the lymph nodes. Even though lymph nodes are in fact commonly assessed in cancer patients to determine disease stage and treatment plan, they are understudied in the context of metastatic progression. To fill this scientific knowledge gap, we propose a Research Center focused on the role of lymph node metastases in tumor-mediated immunosuppression. We hypothesize that lymph node metastasis constitutes an essential, first step in the metastatic cascade of cancer progression. Based on our preliminary findings, we speculate that such metastases act locally upon the adaptive immune system within the nodes to begin to induce systemic tolerance of the tumor. We will explore, compare and test this hypothesis in two malignancies: (i) melanoma and (ii) head and neck squamous cell carcinoma. We have assembled a multidisciplinary team whose coordinated efforts will involve the application of genomic and single-cell in-situ imaging technologies on preclinical and human samples to explore the evidence and mechanisms of the induction of immunosuppression in the lymph nodes. We propose three inter-connected Research Projects that focus our scientific theme on different platforms: murine models (Project 1), high-dimensional in-situ imaging (Project 2), and integrative computational analysis (Project 3). All three projects will utilize a shared resource core dedicated to the acquisition of patient samples and associated clinical annotation and data management (Biospecimen and Data Management Core. These efforts will yield highly multiplexed, multi-scale datasets which will be analyzed by novel bio-computational methods to reconstruct intracellular and intercellular molecular interaction networks in order to identify, then functionally validate, critical mediators of tumor immunosuppression. Our ultimate objective is to advance our understanding of the systemic consequences of lymph node metastases and identify new therapeutic approaches to cancer immunotherapy. Our Research Center is also dedicated to promoting our early investigators as the next generation thought leaders in cancer systems biology. Our Outreach Core will ensure that our Research Center's scientific and methodological advances in applying the principles of cancer systems biology toward the study of tumor- immune interactions are fully disseminated in the cancer research and broader communities.