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 免疫治疗，特别是免疫检查点阻断(Icb)，已经成为最有希望的治疗方法之一。 抗击乳腺癌的工具，具有治疗局部和播散性疾病的优势；以及 预防癌症复发。然而，临床上对ICB的应答率有限：仅有约16% 乳腺癌患者对ICB有反应。ICB通过预防抑制效应抗癌发挥作用 T细胞才能维持强大的抗癌免疫反应。因为适应性免疫系统是 位于淋巴器官内的肿瘤引流淋巴结(TDLN)已被证明含有较高的 肿瘤播散抗原的浓度，我们假设TDLN在促进同源T细胞- 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改变改变了抗原同源物 T细胞相互作用，在临床上损害ICB的反应。在拟议的研究中，我将使用以下工具来验证这一假设 允许纵向监测淋巴流动以及评估T细胞和抗原的动物模型- 在淋巴结内呈现细胞。我将建立自发发生淋巴转移的肿瘤模型 一种稳健的方式，并使用免疫调节干预，以测试询问淋巴结的作用 产生抗癌免疫力。此外，我们将确定原发原位肿瘤的影响，以及 淋巴结内转移对T细胞与同源抗原相互作用的影响 这些参数对ICB疗效的影响。最后，切除原发肿瘤的影响--一个大的 抗癌反应发展的抗癌抗原来源--T细胞表型和ICB 我们将衡量他们的反应。作为一个整体，这项工作有可能为临床护理标准提供信息，以及 提高免疫关卡阻断的效果。 我在使用动物模型研究肿瘤免疫学方面接受了广泛的培训，并在 了解抗原如何从肿瘤转运到淋巴结以影响抗肿瘤免疫反应。 这个项目将利用我的培训，并让我在博士后实验室中增长新的专业知识 顾问-帕德拉博士和穆恩博士-他们是淋巴和血管生物学以及肿瘤领域的领军人物 微环境研究。帕德拉博士的实验室已经开发出最先进的淋巴成像工具，可以精确地 测量淋巴流率，动态活体显微镜观察肿瘤通过淋巴扩散的情况 血管系统和淋巴结内。穆恩博士的实验室已经开发出血管生成的生物工程模型和 肿瘤生物学，以及关于淋巴结和淋巴运输的复杂计算模型。他们加在一起 指导将使我能够成功地完成这项提案的目标。此外，独特的环境 在马萨诸塞州综合医院的斯蒂尔实验室和哈佛医学院将提供 训练我需要迈向独立研究事业的下一步。