Mechanism of dendritic cell differentiation in cancer

描述（由申请人提供）：骨髓细胞的异常分化是癌症的免疫学标志之一。这表现在树突状细胞（DC）的分化受抑制、具有免疫抑制特征的巨噬细胞的出现以及髓源性抑制细胞（MDSC）的积累中。近年来积累的数据清楚地表明，骨髓细胞是免疫系统不能发展和维持抗肿瘤免疫应答的主要贡献者之一。现在很清楚，癌症中的髓样细胞分化受到多种肿瘤源性因子的影响。然而，这种影响的机制仍然难以捉摸。我们和其他人最近确定Jak-STAT 3通路的过度活化是导致DC分化缺陷和MDSC积累的主要原因。它对巨噬细胞功能也至关重要。靶向该途径可以显著改善骨髓细胞分化和抗肿瘤免疫应答。小分子-Jak-STAT 3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，靶向这种对正常细胞分化和存活至关重要的普遍存在的途径将非常困难。因此，重要的是要确定更具体的途径，管理异常骨髓细胞分化的癌症。这不仅可以更好地了解癌症中骨髓细胞异常分化的机制，还可以确定更好的治疗干预靶点。我们已经产生了初步的数据，强烈表明肿瘤介导的DC分化缺陷以及MDSC的积累可以由S100 A9蛋白控制。我们已经获得了S100 A9基因敲除和S100 A9转基因小鼠，这不仅允许剖析这种蛋白在骨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。该提案的总体目标是确定调节癌症中DC和MDSC分化的新机制，并确定MDSC在与炎症相关的肿瘤发展中的作用。为实现这一目标，将努力实现以下具体目标：具体目标1。研究S100 A9在调节DC和髓样细胞分化中的作用;特异性目的2.研究S100 A9对DC和髓样细胞分化的分子机制;特异性目的3.骨髓源性抑制细胞在肿瘤发生中的作用研究。 公共卫生相关性：拟议的研究将调查负责癌症中树突状细胞和髓样细胞异常分化的新机制，这些细胞在癌症的免疫缺陷中发挥关键作用。我们将测试新的假设，即树突状细胞的存在减少和骨髓来源的抑制细胞的积累是由S100 A9蛋白的上调引起的。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。这种机制可能为治疗与癌症相关的免疫缺陷提供了一种新的方法。

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.