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

项目摘要 免疫治疗，特别是免疫检查点阻断（ICB），已成为最有前途的治疗方法之一。 防治乳腺癌的工具，具有治疗局部和扩散性疾病的优势， 防止癌症复发。然而，ICB的反应率在临床上是有限的：只有~16%的人 乳腺癌患者对ICB有反应。ICB通过阻止效应抗癌抑制发挥其作用 T细胞以维持强大的抗癌免疫反应。因为适应性免疫系统 肿瘤引流淋巴结（TDLN）中含有较高的 浓度的肿瘤播散性抗原，我们假设TDLN在促进同源T细胞- 抗原相互作用导致抗癌T细胞的活化，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同源物 T细胞相互作用，在临床上损害ICB反应。在拟议的研究中，我将使用 允许纵向监测淋巴流和评估T细胞和抗原的动物模型， 在淋巴结内呈递细胞。我将自发发展淋巴结转移的癌症模型， 一个强大的方式，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，我们将确定原发性原位肿瘤的影响， 淋巴结内转移的存在对T细胞与淋巴结中相关抗原的相互作用以及 这些参数对ICB疗效的影响。最后，切除原发性肿瘤的影响-一个大的 用于产生抗癌应答-T细胞表型和所得ICB癌抗原来源 将对答复进行衡量。总的来说，这项工作有可能为临床护理标准提供信息， 以提高免疫检查点阻断的功效。 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， 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，让我在我的博士后实验室成长新的专业知识 两位学者--帕德拉博士和穆恩博士--是淋巴和血管生物学以及肿瘤领域的领导者 微环境研究。Padera博士的实验室已经开发出最先进的淋巴成像工具， 测量淋巴流率，并通过淋巴管动态活体显微镜观察肿瘤扩散 脉管系统和淋巴结内。Munn博士的实验室已经开发出血管生成的生物工程模型， 肿瘤生物学，以及淋巴结和淋巴转运的复杂计算模型。其合并 指导将使我能够成功地完成这项建议的目标。此外，独特的环境 在马萨诸塞州总医院和哈佛医学院的斯蒂尔实验室内， 我需要的培训，以采取下一步走向独立的研究生涯。

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.