Mechanism of dendritic cell differentiation in cancer

描述（申请人提供）：骨髓细胞异常分化是癌症的免疫学标志之一。这表现为树突状细胞（DC）分化受到抑制，巨噬细胞出现免疫抑制特征，最显著的是髓源性抑制细胞（MDSC）的积累。近年来积累的数据清楚地表明，骨髓细胞是免疫系统无法发展和维持抗肿瘤免疫反应的主要贡献者之一。现在很清楚，骨髓细胞在癌症中的分化受到多种肿瘤源性因素的影响。然而，这种效应的机制仍然难以捉摸。我们和其他人最近确定，Jak-STAT3通路的过度激活是导致DC分化和MDSC积累缺陷的主要原因。它对巨噬细胞的功能也至关重要。靶向这一途径可能显著改善骨髓细胞分化和抗肿瘤免疫反应。Jak-STAT3的小分子抑制剂目前正在高级临床前研究中进行测试。然而，越来越清楚的是，靶向这种普遍存在的对正常细胞分化和存活至关重要的途径将非常困难。因此，确定控制癌症异常骨髓细胞分化的更具体的途径是很重要的。这不仅可以更好地了解骨髓细胞在癌症中的异常分化机制，而且可以确定更好的治疗干预靶点。我们已经获得的初步数据强烈表明，肿瘤介导的DC分化缺陷以及MDSC的积累可以由S100A9蛋白控制。我们已经获得了S100A9基因敲除和S100A9转基因小鼠，这不仅允许解剖该蛋白在髓细胞分化中的可能作用，而且可以用作鉴定MDSC在肿瘤发生和进展中的作用的工具。本提案的总体目标是确定癌症中调节dc和MDSC分化的新机制，并确定MDSC在炎症相关肿瘤发展中的作用。为实现这一目标，将追求以下具体目标：S100A9在DC和髓细胞分化调控中的作用研究具体目标2。S100A9影响DC和髓细胞分化的分子机制研究具体目标3。髓源性抑制细胞在肿瘤发展中的作用研究。公共卫生相关性：拟议的研究将探索癌症中树突状细胞和骨髓细胞异常分化的新机制，这些细胞在癌症免疫缺陷中起着关键作用。我们将验证新的假设，即树突状细胞的减少和髓源性抑制细胞的积累是由S100A9蛋白上调引起的。我们将研究骨髓源性抑制细胞在肿瘤发生和发展中的作用。这一机制可能为治疗与癌症相关的免疫缺陷提供了一种新的途径。

DESCRIPTION (provided by applicant): Abnormal differentiation of myeloid cells is one of the immunological hallmarks of cancer. This manifests in suppressed differentiation of dendritic cells (DC), appearance of macrophages with immunosuppressive features and most prominently in accumulation of myeloid derived suppressor cells (MDSC). Data accumulated in recent years clearly indicate that myeloid cells are one of the major contributors to inability of immune system to develop and maintain antitumor immune responses. It is now clear that myeloid cell differentiation in cancer is affected by multiple tumor- derived factors. However, the mechanism of this effect remains elusive. We and others have recently determined that hyperactivation of Jak-STAT3 pathway is primarily responsible for the defects in DC differentiation and accumulation of MDSC. It is also critically important for macrophage function. Targeting this pathway may substantially improve myeloid cells differentiation and antitumor immune responses. Small molecules - inhibitors of Jak-STAT3 are currently being tested in advanced pre-clinical studies. However, it became increasingly clear that targeting such ubiquitous pathway, which is critically important for normal cell differentiation and survival will be very difficult. Therefore, it is important to identify more specific pathways that govern abnormal myeloid cell differentiation in cancer. This would not only provide better insight into the mechanisms of abnormal differentiation of myeloid cells in cancer but also may identify better targets for therapeutic intervention. We have generated preliminary data that strongly suggest that tumor-mediated defects in DC differentiation as well as accumulation of MDSC could be controlled by S100A9 protein. We have obtained S100A9 knockout and S100A9 transgenic mice that allowed not only to dissect possible role of this protein in myeloid cell differentiation but also can be used as a tool to identify the role of MDSC in tumor development and progression. Overall goal of this proposal is to identify novel mechanism regulating differentiation of DCs and MDSC in cancer and to identify the role of MDSC in tumor development associated with inflammation. To achieve this goal the following specific aims will be pursued: Specific Aim 1. Investigation the role of S100A9 in regulation of DC and myeloid cell differentiation; Specific Aim 2. Investigation the molecular mechanisms of S100A9 effects on DC and myeloid cell differentiation; Specific Aim 3. Investigation the role of myeloid-derived suppressor cells in tumor development. PUBLIC HEALTH RELEVANCE: Proposed research will investigate novel mechanism responsible for the abnormal differentiation of dendritic cells and myeloid cells in cancer, which play a critical role in immune defects in cancer. We will test novel hypothesis that decreased presence of dendritic cells and accumulation of myeloid-derived suppressor cells is caused by up-regulation of S100A9 protein. We will investigate the role of myeloid-derived suppressor cells in tumor development and progression. This mechanism may suggest a new approach to the treatment of immune defects associated with cancer.