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: 8701873
• 负责人: Scott I. Abrams
• 金额: $ 37.17万
• 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/8701873
• 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.

描述（由申请人提供）：被认为阻碍抗肿瘤免疫反应的过程之一是肿瘤生长过程中骨髓细胞群的出现，称为骨髓源性抑制细胞（MDSC）。这些免疫抑制细胞根据 CD11b 和 Gr-1 细胞表面标记物的特征表达与其他骨髓细胞亚群区分开来。尽管人们对了解 MDSC 如何抑制抗肿瘤免疫机制产生了很大的兴趣，但对于控制其发育的分子事件却知之甚少。因此，拟议的研究将测试这些 CD11b+Gr-1+ MDSC 发展的新假设，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。先前的关键研究揭示了 IRF-8（IRF 转录因子家族的成员）在调节正常骨髓细胞生成中的重要作用。通过小鼠模型中 IRF-8 基因的改变，清楚地阐明了 IRF-8 对骨髓细胞生成的影响。 IRF-8 缺乏会导致骨髓增殖性疾病。总的来说，这些发现表明 IRF-8 缺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，该提案的主要目的是确定 IRF-8 表达与 CD11b+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​​。核心假设是 IRF-8 的功能是阻止肿瘤诱导的 MDSC 发育并获得其促肿瘤活性。进一步假设肿瘤形成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而改变骨髓祖细胞的IRF-8水平。根据我们肿瘤模型中的新初步数据，我们已确定丰富水平的 G-CSF 作为 MDSC 生成的假定肿瘤衍生因子。因此，G-CSF 或其他 STAT3 激活细胞因子引起的肿瘤诱导的 IRF-8 下调可能是 MDSC 发展的新途径的基础。根据我们最近发表的数据，IRF-8 水平在肿瘤诱导的 MDSC 的产生中显着降低，并与肿瘤诱导的 MDSC 的产生呈负相关，中心假设将通过在小鼠模型中追求三个特定目标来检验：两个是机制性的，一个是治疗性的：1）确定 IRF-8 表达与 MDSC 发展之间的因果关系； 2) 确定驱动 IRF-8 下调以及由此产生 MDSC 的肿瘤诱导机制； 3) 确定通过IRF-8过表达阻断MDSC的发育是否会增强免疫治疗的功效。拟议的研究将增强对宿主-肿瘤相互作用的了解，从而提供框架来探索这种新分子途径元素在癌症临床环境中的预后或治疗意义。