Targeting lymph node metastases to prevent cancer progression

针对淋巴结转移预防癌症进展

• 批准号: 9286149
• 负责人: TIMOTHY P PADERA
• 金额: $ 39.5万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-02 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9286149
• 关键词: Address; Adoptive Transfer; Animal Model; Antigens; Arginine; B-Lymphocytes; Biological; Biology; Blood; Blood Vessels; Cancer Patient; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Chronic; Clinical; Complex; Data; Disease; Disease Progression; Disseminated Malignant Neoplasm; Distant; Distant Metastasis; Elements; Enzymes; Equipment; Essential Amino Acids; Event; Exclusion; Goals; Growth; Growth Factor; Hepatocyte; High Endothelial Venule; Home environment; Immune; Immune response; Immune system; Immunologist; Immunology procedure; Immunosuppression; Immunosuppressive Agents; In Vitro; Infiltration; Interdisciplinary Study; Interleukin-10; Invaded; Knowledge; Label; Laboratories; Lesion; Liquid substance; Lung; Lymph; Lymphatic Metastasis; Lymphatic System; Lymphocyte; Lymphocyte Activation; Malignant Lymph Node Neoplasm; Malignant Neoplasms; Measures; Mediating; Metastatic Melanoma; Metastatic Neoplasm to Lymph Nodes; Microscopy; Modeling; Molecular; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Patients; Play; Positioning Attribute; Primary Neoplasm; Process; Production; Prognostic Marker; Radiation; Recommendation; Regimen; Reticular Cell; Risk; Role; Seeds; Signal Transduction; Site; Survival Rate; System; Systemic Therapy; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; Transgenic Animals; Translating; Travel; Tryptophan; Tryptophan 2,3 Dioxygenase; Tumor Cell Migration; Tumor Immunity; Work; adaptive immunity; angiogenesis; arginase; cancer cell; cell motility; cell type; chemokine; experience; image processing; immune function; improved; improved outcome; in vivo; innovation; intravital imaging; intravital microscopy; lymph nodes; macrophage; member; migration; mouse model; neoplastic cell; neutrophil; novel; novel therapeutic intervention; novel therapeutics; outcome forecast; prevent; response; time use; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT Breakthroughs in our knowledge of the molecular and cellular mechanisms regulating metastasis have yet to be broadly translated into improved survival rates for patients with metastatic disease. Lymph node metastasis in a cancer patient brings with it a poorer prognosis and the recommendation for systemic therapy. However, it is unclear whether lymphatic metastases are only predictive or whether they play a role in cancer progression and the emergence of distant metastases. Evidence shows that treating lymph node metastases improves survival in some patients. The work proposed here aims to build a biological understanding of lymph node metastases in order to define their role in disease progression and identify new therapeutic interventions to improve patient survival. Recently, we have shown that lymph node metastases do not require angiogenesis to grow and do not respond to anti-angiogenic therapy. We will build upon our unique expertise by addressing why lymph node metastasis are such strong prognostic indicators and explore how lymph node metastasis drive cancer progression. Specifically, we will test the hypotheses that lymph node metastases disseminate to distant sites (Aim 1) and inhibit the ability of the immune system to develop and maintain anti-tumor immunity (Aim 2). We will accomplish our goals using innovative animal models that allow state-of-the-art intravital microscopy of spontaneous lymph node metastasis. In Aim 1, we will determine whether cancer cells utilize the fibroblastic reticular cell-lined conduit system in lymph nodes to home to blood vessels and spread to distant sites. We will attempt to block this process. In Aim 2, we will determine whether metastatic lymph nodes retain the ability to initiate immune responses to new antigens. Further, we will determine the mechanism of immune suppression in metastatic lymph nodes. We will attempt to increase immune effector function in lymph node metastases to eradicate lymph node disease and stimulate systemic anti-tumor immunity. In completing these aims, we will have better lymph node focused therapeutic options to limit the growth and spread of cancer from lymph nodes and thus provide better outcomes for patients. Critical elements to achieving these goals are intravital imaging equipment, complex animal models and functional immunological assays, all available in the PI’s laboratory. In addition, the assembled team has complementary expertise that will enable them to overcome any problems that occur during the project. Dr. Padera is an expert in intravital microscopy of the lymphatic system and mechanisms of lymph node metastasis. Dr. Carroll is an immunologist with deep knowledge of fluid and cellular transport in lymph nodes as well as adaptive immunity. Dr. Munn has expertise in image processing and quantitative biology with experience in measuring directed cell migration. Each team member, along with our collaborators, will play a critical role in this interdisciplinary research, uniquely positioning us to address these clinically driven questions. With the completion of our studies we will be able to better contain and eradicate lymph node metastasis to extend survival for patients with metastatic cancer.

项目概要/摘要 我们对调节转移的分子和细胞机制的认识尚未取得突破 广泛转化为转移性疾病患者生存率的提高。淋巴结转移 癌症患者的预后较差，建议进行全身治疗。然而，它 目前尚不清楚淋巴转移是否仅具有预测作用或是否在癌症进展中发挥作用 以及远处转移的出现。有证据表明，治疗淋巴结转移可改善 一些患者的生存率。这里提出的工作旨在建立对淋巴结的生物学理解 转移以确定其在疾病进展中的作用并确定新的治疗干预措施 提高患者的生存率。最近，我们发现淋巴结转移不需要血管生成 生长并且对抗血管生成治疗没有反应。我们将通过解决以下问题，利用我们独特的专业知识 为什么淋巴结转移是如此强烈的预后指标并探讨淋巴结转移如何发生 推动癌症进展。具体来说，我们将测试淋巴结转移扩散到的假设 远距离位点（目标 1）并抑制免疫系统发展和维持抗肿瘤免疫的能力 （目标 2）。我们将使用创新的动物模型来实现我们的目标，这些模型允许最先进的活体 镜下观察自发性淋巴结转移。在目标 1 中，我们将确定癌细胞是否利用 淋巴结中成纤维细胞网状细胞排列的导管系统，以血管为家并扩散到远处 网站。我们将尝试阻止此过程。在目标 2 中，我们将确定转移淋巴结是否保留 启动对新抗原的免疫反应的能力。进一步，我们将确定免疫机制 抑制转移淋巴结。我们将尝试增强淋巴结的免疫效应功能 转移以根除淋巴结疾病并刺激全身抗肿瘤免疫力。在完成这些 目标是，我们将有更好的以淋巴结为中心的治疗方案，以限制癌症的生长和扩散 淋巴结，从而为患者提供更好的结果。实现这些目标的关键要素是 活体成像设备、复杂的动物模型和功能性免疫测定，所有这些都可以在 PI的实验室。此外，组建的团队拥有互补的专业知识，使他们能够 克服项目期间出现的任何问题。 Padera 博士是活体显微镜方面的专家 淋巴系统及淋巴结转移机制。卡罗尔博士是一位具有深厚知识的免疫学家 淋巴结中的液体和细胞运输以及适应性免疫的知识。 Munn 博士拥有专业知识 在图像处理和定量生物学领域拥有测量定向细胞迁移的经验。各队 成员以及我们的合作者将在这项跨学科研究中发挥独特的关键作用 让我们能够解决这些临床驱动的问题。完成我们的学习后，我们将能够 更好地遏制和根除淋巴结转移，以延长转移性癌症患者的生存期。