DKK2 regulates NK activation and tumor immunity

DKK2 调节 NK 激活和肿瘤免疫

基本信息

批准号：
10064071
负责人：
Dianqing Wu
金额：
$ 51.33万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064071
关键词：
APC mutation Address Agonist Antibodies Apoptosis Back Binding Proteins Biological Blood Glucose CTLA4 blockade Cancer Model Cause of Death Cell Surface Receptors Cells Clinical Coculture Techniques Colon Carcinoma Colorectal Cancer Colorectal Polyp Complex Developmental Process Diabetes Mellitus Effectiveness Embryonic Development Epithelial Cells Eyelid structure Genetic Goals Homeostasis Human Hyperplasia Immune Immune checkpoint inhibitor Immune system Immunodeficient Mouse Immunotherapy Impairment Interleukin-15 Intestinal Neoplasms Knock-out Knockout Mice Laboratories Lead Low-Density Lipoproteins Malignant Neoplasms Mediating Modeling Mus Mutation NK Cell Activation Natural Killer Cells Nuclear Organogenesis PD-1 blockade PTEN gene Pathway interactions Polyps Process Production Proteins Regulation Reporting Research Resistance Rodent Role Signal Transduction Source Stat5 protein TP53 gene Testing Therapeutic Tissues Tumor Immunity Tumor Promotion Tumor Suppression WNT Signaling Pathway Wnt proteins antitumor effect beta catenin bone cancer cell cancer therapy cytokine glucose metabolism immunomodulatory therapies immunoregulation inhibitor/antagonist interest lipid metabolism melanoma mouse genetics mouse model neoplastic cell neutralizing antibody novel programmed cell death protein 1 stem cell biology therapeutic target tumor tumor progression tumorigenesis

项目摘要

Project Summary: Cancer is a leading cause of death, but recent emergence of immunotherapies including the immune checkpoint inhibitors has offer promising new cancer treatment options. It is also evident that tumor immunity is highly complex and incompletely understood. The better understanding of tumor immune regulation may lead to identification of additional targets for cancer immunomodulatory therapy. In our preliminary studies, we found Dickkopf-2 (DKK2), a protein previously known for its antagonism of the Wnt-β-catenin signaling, as being an inhibitor of natural killer cell activation. Genetic inactivation or antibody-mediated neutralization of DKK2 impedes tumor progression in a mouse genetic intestinal tumor model and syngeneic tumor graft models. The action of DKK2 neutralization on grafted tumor progression depends on immune system, specifically on natural killer (NK) cells, as DKK2 neutralizing antibody loses its effectiveness in the NSG immunodeficient mice and in mice NK1.1+ cells are depleted. DKK2 neutralization increases activation of tumor infiltrated NK cells, accompanied by increases in tumor cell apoptosis. These effects of the antibody can be recapitulated in a co- culture of primary mouse NK cells and tumor cells. Moreover, DKK2 protein can directly inhibit activation of NK cells by IL-15 probably by impairing STAT5 nuclear localization. These preliminary results together suggest a hypothesis that DKK2 may promote tumor formation by inhibiting IL-15 signaling and NK cell activation. In this study we will extend our preliminary studies to further test the hypothesis. The specific aims are: 1) To investigate how DKK2 suppresses NK cell activation. 2) To further characterize the mechanism of action for DKK2 inhibition to impede tumor progression. 3) To further evaluate the therapeutic potentials of DKK2 neutralization in cancer treatment using mouse models.

项目概要：癌症是死亡的主要原因，但最近出现的免疫疗法，包括免疫疗法检查点抑制剂提供了有前景的新癌症治疗选择，肿瘤免疫也很明显。高度复杂且不完全了解可能会导致对肿瘤免疫调节的更好理解。在我们的初步研究中，我们确定了癌症免疫调节治疗的其他靶点。发现了 Dickkopf-2 (DKK2)，这是一种以前因其拮抗 Wnt-β-catenin 信号而闻名的蛋白质，如是自然杀伤细胞激活的抑制剂或抗体介导的中和作用。 DKK2 在小鼠遗传性肠肿瘤模型和同基因肿瘤移植模型中阻碍肿瘤进展。 DKK2 中和对移植肿瘤进展的作用取决于免疫系统，特别是自然杀伤 (NK) 细胞，因为 DKK2 中和抗体在 NSG 免疫缺陷小鼠中失去效力在小鼠中，NK1.1+ 细胞被耗尽，肿瘤浸润的 NK 细胞的 DKK2 中和激活增加。伴随着肿瘤细胞凋亡的增加，抗体的这些作用可以概括为共同的。原代小鼠NK细胞和肿瘤细胞的培养，而且DKK2蛋白可以直接抑制NK的激活。 IL-15 可能通过损害 STAT5 核定位来影响细胞。假设 DKK2 可能通过抑制 IL-15 信号传导和 NK 细胞激活来促进肿瘤形成。研究我们将扩展我们的初步研究以进一步检验假设。研究 DKK2 如何抑制 NK 细胞活化 2) 进一步表征其作用机制。抑制DKK2以阻止肿瘤进展3)进一步评估DKK2的治疗潜力。使用小鼠模型进行癌症治疗中和。