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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要免疫疗法，特别是免疫检查点阻断（ICB），已成为最有前途的疗法之一对抗乳腺癌的工具，具有治疗局部和播散性疾病的优势，以及然而，ICB 的临床缓解率有限：仅约 16%。乳腺癌患者对 ICB 的反应是通过阻止效应抗癌的抑制来发挥其作用。 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这样的。位于淋巴器官内，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，我们追求 TDLN 在促进同源 T 细胞中的作用抗原相互作用导致抗癌 T 细胞激活，这是 ICB 反应的先决条件。发现肿瘤介导的流体动力学和局部微环境的改变改变了抗原同源 T 细胞相互作用，会损害临床上的 ICB 反应。在拟议的研究中，我将使用该假设来检验这一假设。允许纵向监测淋巴流动并评估 T 细胞和抗原的动物模型我将展示淋巴结内自发发生淋巴结转移的癌症模型。以稳健的方式并使用免疫调节干预措施来测试淋巴结的作用此外，我们将确定原发性原位肿瘤的影响，以及淋巴结内转移的存在对 T 细胞与淋巴结中同源抗原的相互作用的影响这些参数对 ICB 疗效的影响最后是切除原发肿瘤的影响——一个很大的影响。用于产生抗癌反应的癌症抗原来源——T 细胞表型和由此产生的 ICB 总体而言，这项工作有可能为临床护理标准提供信息，并且提高免疫检查点封锁的功效。我在使用动物模型研究肿瘤免疫学方面接受过广泛的培训，并且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。该项目将利用我的培训，让我在博士后实验室中获得新的专业知识顾问 - Padera 博士和 Munn 博士 - 他们是淋巴和血管生物学以及肿瘤领域的领导者 Padera 博士的实验室开发了最先进的淋巴成像工具，可以精确地进行微环境研究。测量淋巴流速，并通过动态活体显微镜观察肿瘤通过淋巴管的传播 Munn 博士的实验室开发了血管生成和淋巴结内的生物工程模型。肿瘤生物学，以及淋巴结和淋巴运输的复杂计算模型。指导将使我能够成功地完成该提案的目标此外，独特的环境。马萨诸塞州总医院和哈佛医学院的斯蒂尔实验室将提供培训我需要向独立研究生涯迈出下一步。