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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.

项目总结：癌症是导致死亡的主要原因，但最近出现了包括免疫在内的免疫疗法检查点抑制剂提供了有希望的新癌症治疗选择。同样明显的是，肿瘤免疫是高度复杂和不完全理解。对肿瘤免疫调节的更好理解可能会导致旨在确定癌症免疫调节治疗的其他靶点。在我们的初步研究中，我们发现了Dickkopf-2(DKK2)，这是一种以前以拮抗Wnt-β-Catenin信号而闻名的蛋白质，AS 是自然杀伤细胞激活的抑制因子。基因失活或抗体介导的中和在小鼠遗传性肠道肿瘤模型和同基因肿瘤移植模型中，DKK2阻碍肿瘤进展。 DKK2中和对移植瘤进展的作用依赖于免疫系统，特别是自然杀伤(NK)细胞作为DKK2中和抗体在NSG免疫缺陷小鼠中失效而在小鼠中，NK1.1+细胞被耗尽。DKK2中和可增加肿瘤浸润性NK细胞的激活，伴随着肿瘤细胞凋亡率的增加。抗体的这些作用可以用一个共同的- 原代培养小鼠NK细胞和肿瘤细胞。此外，DKK2蛋白还可直接抑制NK细胞的活化 IL-15可能通过破坏STAT5的核定位而影响细胞的功能。这些初步结果综合起来表明假说DKK2可能通过抑制IL-15信号和NK细胞激活促进肿瘤的形成。在这我们将扩大我们的初步研究，以进一步检验这一假说。具体目标是：1) 研究DKK2是如何抑制NK细胞活化的。2)进一步描述作用机制抑制DKK2以阻止肿瘤进展。3)进一步评价DKK2的治疗潜力用小鼠模型进行癌症治疗中的中和。