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

描述(由申请人提供)：在被认为阻碍抗肿瘤免疫反应的过程中，肿瘤生长过程中出现了髓系细胞群，称为髓系源抑制细胞(MDSC)。这些免疫抑制细胞因其CD11b和Gr-1细胞表面标志的特征表达而有别于其他髓系细胞亚群。尽管人们对MDSC如何抑制抗肿瘤免疫机制有相当大的兴趣，但对于支配其发展的分子事件却知之甚少。因此，拟议的研究将检验CD11b+Gr-1+MDSC发展的新假说，该假说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。以前的关键研究已经揭示了IRF-8，IRF转录因子家族的成员，在调节正常的骨髓生成中起着至关重要的作用。IRF-8在小鼠模型中的基因变化已经清楚地阐明了IRF-8在骨髓生成中的影响。IRF-8缺乏会导致骨髓增生性疾病。总之，这些发现表明，IRF-8缺失或下调对骨髓单核细胞的发育和分化具有深刻的病理后果。因此，这项建议的主要目的是确定IRF-8表达和CD11b+Gr-1+MDSC生成之间的因果联系，从概念上讲，这可能类似于在IRF-8缺失小鼠中观察到的异常骨髓生成。中心假设是，IRF-8的功能是阻止肿瘤诱导的MDSC的发展和其促肿瘤活性的获得。进一步的假设是，肿瘤过程通过某些肿瘤来源的骨髓细胞生长因子的不适当产生和作用来改变髓系祖细胞的IRF-8水平。基于我们肿瘤模型的新的初步数据，我们已经确认大量的G-CSF水平是一种假定的肿瘤衍生因子，产生MDSC。因此，肿瘤诱导的IRF-8被G-CSF或其他STAT3激活的细胞因子下调可能是MDSC发展的新途径。以我们最近发表的数据为指导，即IRF-8水平在肿瘤诱导的MDSC的产生中显著降低，且与之呈负相关，将在小鼠模型中通过追求三个特定目标来检验中心假说：两个将是机械性的，一个将是治疗性的：1)确定IRF-8的表达与MDSC发展之间的因果联系；2)确定导致IRF-8下调表达和MDSC的产生的肿瘤诱导机制；以及3)确定通过IRF-8的过表达来阻断MDSC的发展是否会提高免疫治疗的疗效。这项拟议的研究将加强对宿主-肿瘤相互作用的了解，从而为探索这一新的分子途径的元件在癌症临床环境中的预后或治疗意义提供框架。 公共卫生相关性：髓系来源的抑制细胞(MDSC)是最近发现的一组白细胞，在某些类型的实体癌症患者体内积聚，被认为是有效抗癌免疫反应的重要屏障。MDSC通常通过CD11b和Gr-1两种细胞表面标志物的独特表达来识别。尽管人们对MDSC阻断免疫的机制有很大的兴趣，但对调节其发育的过程却知之甚少。我们的研究将探索这样一个概念，即这些细胞之所以出现，是因为癌细胞导致一种名为干扰素调节因子-8(IRF-8)的主控基因发生深刻变化，该基因对于控制髓系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，并将与癌症和设计新的预后或治疗肿瘤学方案高度相关。

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.