Determining the role of myeloid cells in establishing the pre-metastatic niche in pancreatic cancer

确定骨髓细胞在建立胰腺癌转移前生态位中的作用

• 批准号: 10063306
• 负责人: Samantha Blake Kemp
• 金额: $ 3.12万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063306
• 关键词: Address; Alzheimer' s Disease; Animals; Apolipoprotein E; Atherosclerosis; Biocompatible Materials; Biological Assay; Blood; Bone Marrow; Breast Cancer Model; CD8-Positive T-Lymphocytes; Cells; Coculture Techniques; Complex; Cytotoxic T-Lymphocytes; Data; Disease; Distal; Engineering; Fibroblasts; Goals; Growth; Histology; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunosuppression; Immunotherapy; Impairment; In Vitro; Individual; Inflammatory; Isogenic transplantation; Knock-out; Knockout Mice; Laboratories; Lead; Leucocytic infiltrate; Malignant Neoplasms; Malignant neoplasm of pancreas; Metastatic to; Modeling; Monitor; Mus; Myelogenous; Myeloid Cells; Nature; Neoplasm Metastasis; Organ; Pancreatic Ductal Adenocarcinoma; Patients; Polymers; Population; Primary Neoplasm; Research; Role; Site; Survival Rate; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Tumor Markers; Tumor-associated macrophages; Tumor-infiltrating immune cells; anti-PD-1; apolipoprotein E-1; biomarker panel; cell type; checkpoint therapy; cytotoxic CD8 T cells; differential expression; effective therapy; exhaustion; experimental study; functional status; immune activation; immune checkpoint blockade; immunosuppressed; in vivo; macrophage; melanoma; mouse model; neoplastic cell; novel; outcome forecast; overexpression; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; prevent; scaffold; success; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT The most prevalent type of pancreatic cancer, pancreatic ductal adenocarcinoma (PDA) is a lethal cancer which has not seen substantial progress in survival rate in over four decades. Patients present most often with metastatic disease, for which there are no effective therapies. The disease is characterized by a complex tumor microenvironment that consists of fibroblasts and infiltrating immune cells, of a suppressive nature. This suppressive, cellular cross-talk exists both in the primary tumor and at sites of metastases. It is known that other cell types, such as immune cells, arrive to these distal sites preceding tumor cell dissemination. These sites are referred to as the pre-metastatic niche and remodel the distal organs to be favorable for tumor cell colonization and growth. Recently, immune checkpoint inhibitors have shown success in other cancers, specifically melanoma, but have shown little success in pancreatic cancer. Our lab, and others, has shown the importance of myeloid cells in establishing immune suppression at the primary tumor. What remains unknown is how the pre-metastatic niche is established. My data show that Apolipoprotein E (ApoE) is differentially expressed in the pre-metastatic niche of tumor-bearing animals. This niche has a robust myeloid population that expresses ApoE, and is sparsely populated by cytotoxic T cells, indicative of immune suppression at these distal sites. The overall objective is to understand the cellular interactions that lead to the establishment of the immunosuppressive pre- metastatic niche in pancreatic cancer. The central hypothesis is that ApoE contribute to the immunosuppressive nature of the pancreatic cancer microenvironment at the primary and metastatic sites (Aim 1) and modulates macrophage polarization and function of TAMs, regulating T cell activity (Aim 2). To test my hypothesis, I will use biomaterial scaffolds to study the pre-metastatic niche in vivo. Scaffolds are able to recapitulate the pre-metastatic niche and will allow me to characterize the cellular infiltrate and discover novel targets to block pre-metastatic niche establishment. These experiments will give mechanistic data on the role of myeloid cells in establishing the pre-metastatic niche in pancreatic cancer.

项目总结/摘要 胰腺癌的最常见类型，胰腺导管腺癌（PDA）是一种致死性癌症， 40多年来，存活率没有实质性进展。患者最常表现为 转移性疾病，对此没有有效的治疗方法。这种病的特点是肿瘤复杂 微环境由成纤维细胞和浸润性免疫细胞组成，具有抑制性质。这 抑制性细胞串扰存在于原发肿瘤和转移部位。已知其它 细胞类型如免疫细胞在肿瘤细胞播散之前到达这些远端部位。这些网站是 并重塑远端器官以有利于肿瘤细胞定植 和增长最近，免疫检查点抑制剂在其他癌症中取得了成功，特别是 黑色素瘤，但在胰腺癌方面收效甚微。我们的实验室和其他实验室已经证明了 骨髓细胞在原发性肿瘤中建立免疫抑制。目前尚不清楚的是， 转移前生态位已建立。我的数据表明，载脂蛋白E（ApoE）的差异表达， 肿瘤动物的转移前生态位。这个小生境具有表达ApoE的强大的骨髓群体， 并且细胞毒性T细胞稀疏分布，表明在这些远端部位的免疫抑制。整体 目的是了解导致建立免疫抑制前体的细胞相互作用， 胰腺癌的转移小生境。中心假设是ApoE有助于 原发性和转移性胰腺癌微环境的免疫抑制性质 位点（Aim 1）并调节巨噬细胞极化和TAM的功能，调节T细胞活性 (Aim 2）。为了验证我的假设，我将使用生物材料支架来研究体内转移前的小生境。支架 能够概括转移前的小生境，并允许我描述细胞浸润的特征， 发现新的靶点来阻断转移前的小生境建立。这些实验将提供机械数据 骨髓细胞在胰腺癌转移前小生境形成中的作用。