DKK2 regulates NK activation and tumor immunity

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 检查点抑制剂提供了有希望的新的癌症治疗选择。同样明显的是，肿瘤免疫是 非常复杂而且不完全理解。对肿瘤免疫调节的更好理解可能会导致 涉及癌症免疫调节治疗的其它靶点的鉴定。在初步研究中，我们 发现Dickkopf-2（DKK 2），一种以前以拮抗Wnt-β-catenin信号传导而闻名的蛋白质， 作为自然杀伤细胞激活的抑制剂。基因失活或抗体介导的中和 DKK 2在小鼠遗传性肠道肿瘤模型和同基因肿瘤移植模型中阻碍肿瘤进展。 DKK 2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DKK 2中和抗体在NSG免疫缺陷小鼠中失去效力 而在小鼠中，NK 1.1+细胞被耗尽。DKK 2中和增加肿瘤浸润的NK细胞的活化， 伴随着肿瘤细胞凋亡的增加。抗体的这些作用可以在共- 原代小鼠NK细胞和肿瘤细胞的培养。此外，DKK 2蛋白可直接抑制NK细胞的活化， IL-15可能通过损害STAT 5核定位而影响细胞。这些初步结果表明， DKK 2可能通过抑制IL-15信号传导和NK细胞活化促进肿瘤形成的假说。在这 我们将扩展我们的初步研究，以进一步验证这一假设。具体目标是：（1） 研究DKK 2如何抑制NK细胞活化。2)为了进一步描述作用机制， DKK 2抑制以阻止肿瘤进展。3)进一步评价DKK 2的治疗潜力 使用小鼠模型进行癌症治疗中的中和。

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.