Dissecting the role of Notch signaling in the pancreatic cancer microenvironment.

项目摘要/摘要 胰腺癌的特点是免疫抑制的肿瘤微环境对整体 在这种致命的恶性肿瘤中表现出治疗耐药性。尽管Notch信号在细胞的生长过程中是不可或缺的 胰腺肿瘤及其在免疫抑制肿瘤建立和维持中的作用 微环境尚不清楚。长期目标是定义像Notch这样的细胞间信号通路的作用 在胰腺癌的治疗耐药中。这个应用程序的总体目标是定义Notch如何 调节胰腺肿瘤微环境中髓系细胞的极化，从而调节T细胞的极化 调节其免疫抑制性质。该应用程序的中心假设是Notch充当 促进免疫抑制髓系建立和衰竭的关键调控途径 无能T细胞群。这一建议的基本原理是，理解机制基础和影响 对胰腺肿瘤微环境中Notch信号的研究将确定增敏胰腺的新方法 癌症到现有的治疗方法，包括免疫疗法。 核心假设将通过三个具体目标进行检验- 1.剖析胰腺癌微环境中的Notch信号； 2.明确Notch信号在髓系极化和功能中的作用机制和直接作用； 2.靶向Notch信号通路减轻胰腺癌免疫抑制 我们将使用人类和小鼠胰腺癌样本的组合，基因工程小鼠 将使用模型、原位肿瘤模型以及人和小鼠肿瘤细胞系。此外，我们还将使用 人类器官和癌症相关成纤维细胞，以及患者匹配的免疫细胞。凹槽 信号将通过体内和体外的遗传和药理学方法被破坏，以确定其作用 在骨髓室功能方面。拟议的工作具有创新性，因为它定义了Notch的新角色 胰腺癌已知的上皮功能以外的信号转导。 它具有重要的意义，因为它允许潜在的开发新的免疫调节疗法来治疗这种疾病 致命的疾病。

Project Summary/Abstract Pancreatic cancer is marked by an immunosuppressive tumor microenvironment contributing to the overall therapeutic resistance seen in this deadly malignancy. Although Notch signaling is integral in the progression of pancreatic neoplasia, its role in the establishment and maintenance of the immunosuppressive tumor microenvironment is unclear. The long-term goal is to define the role of intercellular signaling pathways like Notch in the treatment resistance in pancreatic cancer. The overall objective of this application is to define how Notch regulates myeloid and, as a consequence, T cell polarization in the pancreatic tumor microenvironment to regulate its immunosuppressive nature. The central hypothesis of the application is that Notch serves as one of the key regulatory pathways promoting the establishment of immunosuppressive myeloid and exhausted or anergic T cell populations. The rationale for this proposal is that understanding the mechanistic basis and effects of Notch signaling on the pancreatic tumor microenvironment will identify new approaches to sensitize pancreatic cancer to existing therapies including immunotherapy. The central hypothesis will be tested through three specific aims – 1. Dissect Notch signaling in the pancreatic cancer microenvironment; 2. Define the mechanism and direct effects of Notch signaling on myeloid polarization and function; 2. Target Notch signaling to alleviate immune suppression in pancreatic cancer. We will use a combination of human and mouse pancreatic cancer samples, genetically engineered mouse models, orthotopic tumor models, and human and murine tumor cell lines will be used. In addition, we will use human organoids and cancer associated fibroblasts, together with patient-matched immune cells. Notch signaling will be disrupted via genetic and pharmacologic approaches both in vivo and in vitro to define its role in myeloid compartment function. The proposed work is innovative because it defines novel roles of Notch signaling in pancreatic cancer outside its known epithelial function. It is significant because it allows for the potential development of new immunomodulatory treatments for this deadly disease.