Enhanced antigen-lymphocyte interactions to improve immune checkpoint blockade in breast cancer

增强抗原-淋巴细胞相互作用以改善乳腺癌中的免疫检查点阻断

• 批准号: 10535068
• 负责人: Meghan O'Melia
• 金额: $ 6.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-10 至 2025-07-09
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10535068
• 关键词: Adaptive Immune System; Animal Model; Antigen-Presenting Cells; Antigens; Biology; Biomedical Engineering; Blood Vessels; Breast Cancer Patient; Breast Cancer Treatment; Cancer Model; Cancer Patient; Cell Communication; Cell Proliferation; Cells; Clinical; Computer Models; Development; Disease; Environment; Event; Excision; Failure; Fellowship; General Hospitals; Generations; Imaging Device; Imaging Techniques; Immune; Immune response; Immunotherapy; Impairment; In Situ; Interruption; Intervention; Label; Laboratories; Lead; Liquid substance; Location; Lymphatic; Lymphatic function; Lymphocyte; Lymphocyte antigen; Malignant Neoplasms; Massachusetts; Measures; Mechanics; Mediating; Melia; Memory; Metastatic Neoplasm to Lymph Nodes; Modeling; Molecular; Monoclonal Antibodies; Neoplasm Metastasis; Patients; Phenotype; Physiological; Primary Neoplasm; Procedures; Process; Production; Recurrent disease; Research; Resected; Role; Source; Spatial Distribution; T cell anergy; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Training; Tumor Antigens; Tumor Biology; Tumor Immunity; Work; anergy; angiogenesis; animal imaging; anti-cancer; anti-tumor immune response; cancer cell; cancer recurrence; cancer therapy; career; cell killing; clinical effect; draining lymph node; exhaustion; experimental study; fight against; immune activation; immune checkpoint; immune checkpoint blockade; immunoregulation; improved; intravital microscopy; lymph flow; lymph nodes; lymphatic circulation; lymphatic imaging; lymphatic vasculature; lymphocyte trafficking; lymphoid organ; malignant breast neoplasm; medical schools; novel; prevent; response; standard of care; stem; tool; tumor; tumor immunology; tumor microenvironment

Project Summary Immunotherapy, and in particular immune checkpoint blockade (ICB), has emerged as one of the most promising tools in the fight against breast cancer, with the advantages of treating both local and disseminated disease, and protecting against cancer recurrence. However, response rates to ICB have been limited clinically: only ~16% of breast cancer patients respond to ICB. ICB exerts its effects by preventing the suppression of effector anti-cancer T cells in order to maintain a strong anti-cancer immune response. Because the adaptive immune system is housed within lymphoid organs, and tumor draining lymph nodes (TDLNs) have been shown to contain higher concentrations of tumor-disseminated antigen, we hypothesize a role for TDLNs in facilitating cognate T cell- antigen interactions that lead to activation of anti-cancer T cells that are prerequisite for ICB response. I hypothesize that tumor-mediated alterations in fluid dynamics and local microenvironments alter antigen-cognate T cell interactions, which impairs ICB responses clinically. In the proposed study, I will test this hypothesis using animal models which allow for longitudinal surveillance of lymph flow and the assessment of T cells and antigen- presenting cells within lymph nodes. I will cancer models that spontaneously develop lymph node metastases in a robust manner and use immunomodulatory interventions to test interrogate the role of lymph nodes in generating anti-cancer immunity. Further, we will determine the effects of primary in situ tumors, and the presence of intra-lymph node metastases on the T cell interactions with cognate antigen in lymph nodes and the impacts of these parameters on ICB efficacy. Finally, the impacts of removal of the primary tumor—a large source of cancer antigen for development of anti-cancer responses—on T cell phenotypes and resulting ICB responses will be measured. As a whole, this work has the potential to both inform clinical standard of care, and to improve the efficacy of immune checkpoint blockade. I have extensive training in the use of animal models to investigate the tumor immunology, and in understanding how antigen is transported from tumors to lymph nodes to impact anti-tumor immune responses. This project will leverage my training and allow me to grow new expertise in the labs of my postdoctoral advisors—Dr. Padera and Dr. Munn—who are leaders in lymphatic and vascular biology as well as tumor microenvironment research. Dr. Padera’s lab has developed state-of-the-art lymphatic imaging tools to precisely measure lymph flow rate, and dynamic intravital microscopy of tumor dissemination through lymphatic vasculature and within lymph nodes. Dr. Munn’s lab has developed bioengineered models of angiogenesis and tumor biology, and sophisticated computational models of lymph nodes and lymphatic transport. Their combined guidance will allow me to successfully complete the aims of this proposal. Furthermore, the unique environment within the Steele Laboratories at Massachusetts General Hospital and Harvard Medical School will provide the training I need to take the next step toward an independent research career.

项目摘要 免疫疗法，尤其是免疫检查点封锁（ICB），已经成为最有望的 抗击乳腺癌的工具，具有治疗局部和传播疾病的优势， 防止癌症复发。但是，临床上对ICB的回应率受到限制：只有约16％ 乳腺癌患者对ICB的反应。 ICB通过防止抑制效应抗癌来发挥其影响 T细胞以维持强烈的抗癌免疫增强响应。因为适应性免疫响应是 嵌合在淋巴机构中，肿瘤排干淋巴结（TDLN）已显示出较高的 肿瘤释放抗原的浓度，我们假设TDLN在促进同源T细胞中的作用 导致抗癌T细胞激活的抗原相互作用，这是ICB反应的先决条件。我 假设肿瘤介导的流体动力学和局部微环境的改变改变了抗原 - 立场 T细胞相互作用，临床上会损害ICB反应。在拟议的研究中，我将使用 动物模型允许对淋巴流量进行纵向监测以及T细胞和抗原的评估 淋巴结内的细胞。我将在赞助中发展淋巴结转移的癌症模型 强大的方式并使用免疫调节干预措施来测试淋巴结在 产生抗癌免疫力。此外，我们将确定原发性原位肿瘤的影响，并确定 在T细胞相互作用与淋巴结中的同源抗原相互作用上存在淋巴结转移和 这些参数对ICB效率的影响。最后，去除原发性肿瘤的影响 - 大型 抗癌反应发展的癌症抗原的来源 - T细胞表型和由此产生的ICB 响应将被衡量。总体而言，这项工作有可能为临床护理标准提供信息， 提高免疫检查点封锁的效率。 我在使用动物模型来研究肿瘤免疫学方面接受了广泛的培训 了解如何将抗原从肿瘤传输到淋巴结，以影响抗肿瘤免疫复杂。 该项目将利用我的培训，并允许我在博士后的实验室中发展新的专业知识 顾问-DR。 Padera和Munn博士 - 淋巴和血管生物学领域的领导者以及肿瘤 微环境研究。 Padera博士的实验室已经开发了最先进的淋巴成像工具来精确 测量淋巴传播淋巴传播的淋巴流量和动态插入式显微镜 脉管系统和淋巴结内。 Munn博士的实验室开发了生物工程的血管生成模型和 肿瘤生物学以及淋巴结和淋巴运输的复杂计算模型。他们的结合 指导将使我能够成功完成该提案的目标。此外，独特的环境 在马萨诸塞州综合医院和哈佛医学院的斯蒂尔实验室内，将提供 培训我需要迈出独立研究职业的下一步。