IRF-8 as a Negative Regulator of CD11b+Gr-1+ Myeloid Cell Production and Function

IRF-8 作为 CD11b Gr-1 骨髓细胞产生和功能的负调节因子

• 批准号: 8105762
• 负责人: Scott I. Abrams
• 金额: $ 36.82万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105762
• 关键词: CMV promoter; Cell surface; Cells; Cellular biology; Characteristics; Clinical; Data; Development; Down-Regulation; Elements; Event; Family; Gene Mutation; Generations; Genes; Genetic Transcription; Goals; Granulocyte Colony-Stimulating Factor; Growth Factor; Hematopoietic; IFN consensus sequence binding protein; ITGAM gene; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Knockout Mice; Knowledge; Laboratories; Leukocytes; Link; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; Myeloproliferative disease; Neoplastic Processes; Pathologic; Pathway interactions; Patients; Play; Population; Process; Production; Property; Publishing; Regulation; Relative (related person); Research; Resistance; Role; STAT3 gene; Signal Transduction; Solid; Stat3 protein; Suppressor-Effector T-Lymphocytes; Testing; Therapeutic; Tissues; Transgenes; Transgenic Mice; Transgenic Organisms; Translating; Tumor Escape; Tumor-Derived; Work; base; cancer cell; cancer immunotherapy; cell type; cytokine; design; host neoplasm interaction; immune activation; improved; interest; loss of function; macrophage; member; mouse model; neoplastic cell; novel; population based; pre-clinical; prevent; progenitor; prognostic; promoter; response; therapeutic target; transcription factor; tumor; tumor growth; tumor immunology; tumorigenic

DESCRIPTION (provided by applicant): Among processes believed to impede the antitumor immune response is the emergence of myeloid cell populations during tumor growth, termed myeloid-derived suppressor cells (MDSC). These immune suppressing cells are distinguished from other myeloid subsets based on their characteristic expression of both CD11b and Gr-1 cell surface markers. Although considerable interest has been dedicated to understanding how MDSC inhibit antitumor immune mechanisms, much less is known regarding the molecular events that govern their development to begin with. Thus, the proposed research will test a novel hypothesis by which these CD11b+Gr-1+ MDSC develop, one which reflects a new functional role for interferon regulatory factor-8 (IRF-8) in tumor immunology. Previous key studies have revealed an essential role for IRF-8, a member of the IRF family of transcription factors, in regulating normal myelopoiesis. The impact of IRF-8 in myelopoiesis has been clearly illuminated by alteration of the gene in mouse models. IRF-8 deficiency leads to myeloproliferative disorders. Collectively, these findings indicate that IRF-8 loss or down-regulation has profound pathologic consequences on myelo-monocytic development and differentiation. Therefore, the primary objective of this proposal is to determine the causal link between IRF-8 expression and CD11b+Gr-1+ MDSC generation, which conceptually may be analogous to the aberrant myelopoiesis observed in IRF-8 null mice. The central hypothesis is that IRF-8 functions to block tumor-induced MDSC development and acquisition of their pro-tumorigenic activities. It is further hypothesized that the neoplastic process alters IRF-8 levels of myeloid progenitors through the inappropriate production and action of certain tumor-derived myelopoietic growth factors. Based on new preliminary data in our tumor models, we have identified abundant levels of G-CSF as a putative tumor-derived factor of MDSC generation. Thus, tumor-induced IRF-8 down-regulation by G-CSF or other STAT3-activating cytokines may underlie a novel pathway for MDSC development. Guided by our recently published data that IRF-8 levels are strongly reduced in, and inversely correlated with, the generation of tumor-induced MDSC, the central hypothesis will be tested by pursuing three specific aims in mouse models: two will be mechanistic and one will be therapeutic in scope: 1) Determine the causal link between IRF-8 expression and MDSC development; 2) Identify tumor-induced mechanisms that drive IRF-8 down-regulation and the resultant production of MDSC; and 3) To determine whether blocking MDSC development through IRF-8 over-expression will enhance immunotherapy efficacy. The proposed research will enhance knowledge of the host-tumor interaction and, thus, provide the framework to explore the prognostic or therapeutic significance of elements of this new molecular pathway in cancer clinical settings. PUBLIC HEALTH RELEVANCE: Myeloid-derived suppressor cells (MDSC) are a recently discovered population of white blood cells that accumulate in patients with certain types of solid cancers and are thought to embody a significant barrier to an effective anti-cancer immune response. MDSC are typically identified by their unique expression of two cell surface markers, known as CD11b and Gr-1. Although much interest has been devoted to understanding mechanisms by which MDSC block immunity, much less is known regarding the processes that regulate their development. Our research will explore the concept that these cells arise because cancer cells cause a profound alteration in a 'master gene', called interferon regulatory factor-8 (IRF-8) that is essential for controlling fundamental properties of the myeloid cell family and preventing the generation of MDSC. This work will advance our understanding of mechanisms of immune suppression, and will be highly relevant to cancer and the design of novel prognostic or therapeutic oncologic options.

描述（由申请人提供）：在被认为阻碍抗肿瘤免疫应答的过程中，肿瘤生长期间出现髓样细胞群，称为髓源性抑制细胞（MDSC）。这些免疫抑制细胞基于其CD 11b和Gr-1细胞表面标志物的特征性表达而与其他骨髓亚群区分开。尽管人们对MDSC如何抑制抗肿瘤免疫机制有着相当大的兴趣，但关于控制其发展开始的分子事件知之甚少。因此，拟议的研究将测试这些CD 11b +Gr-1+ MDSC发育的新假设，该假设反映了干扰素调节因子-8（IRF-8）在肿瘤免疫学中的新功能作用。先前的关键研究已经揭示了IRF-8（IRF家族转录因子的成员）在调节正常骨髓生成中的重要作用。IRF-8在骨髓生成中的影响已通过小鼠模型中基因的改变而清楚地阐明。IRF-8缺乏导致骨髓增生性疾病。总的来说，这些发现表明IRF-8丢失或下调对骨髓单核细胞发育和分化具有深远的病理后果。因此，本提案的主要目的是确定IRF-8表达与CD 11b +Gr-1+ MDSC生成之间的因果关系，这在概念上可能类似于在IRF-8缺失小鼠中观察到的异常骨髓生成。中心假设是IRF-8的功能是阻断肿瘤诱导的MDSC发育和获得其促肿瘤活性。进一步假设肿瘤过程通过某些肿瘤源性骨髓生成生长因子的不适当产生和作用改变骨髓祖细胞的IRF-8水平。基于我们的肿瘤模型中的新的初步数据，我们已经确定了丰富水平的G-CSF作为MDSC生成的假定肿瘤衍生因子。因此，肿瘤诱导的IRF-8下调G-CSF或其他STAT 3激活细胞因子可能是MDSC发展的新途径的基础。根据我们最近发表的数据，即IRF-8水平在肿瘤诱导的MDSC的产生中强烈降低，并且与肿瘤诱导的MDSC的产生负相关，将通过在小鼠模型中追求三个特定目标来测试中心假设：两个将是机制性的，一个将是治疗性的范围：1）确定IRF-8表达和MDSC发展之间的因果关系; 2）鉴定驱动IRF-8下调和由此产生的MDSC产生的肿瘤诱导机制;和3）确定通过IRF-8过表达阻断MDSC发育是否将增强免疫治疗功效。拟议的研究将增强对宿主-肿瘤相互作用的认识，从而为探索这种新分子途径的元素在癌症临床环境中的预后或治疗意义提供框架。 公共卫生关系：髓源性抑制细胞（MDSC）是最近发现的白色血细胞群体，其在患有某些类型的实体癌的患者中积累，并且被认为体现了有效抗癌免疫应答的显著屏障。MDSC通常通过其独特的两种细胞表面标志物（称为CD 11b和Gr-1）的表达来鉴定。尽管人们对了解MDSC阻断免疫的机制很感兴趣，但对调节其发展的过程知之甚少。我们的研究将探索这样一个概念，即这些细胞的产生是因为癌细胞引起了一个称为干扰素调节因子-8（IRF-8）的“主基因”的深刻改变，该基因对于控制骨髓细胞家族的基本特性和防止MDSC的产生至关重要。这项工作将促进我们对免疫抑制机制的理解，并将与癌症和新的预后或治疗肿瘤学选择的设计高度相关。