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髓系细胞群，称为髓系来源抑制细胞（MDSC）。基于CD11b和Gr-1细胞表面标记物的特征性表达，这些免疫抑制细胞与其他髓细胞亚群区别开来。尽管人们对MDSC如何抑制抗肿瘤免疫机制有相当大的兴趣，但对控制其发展的分子事件知之甚少。因此，本研究将验证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在调节正常骨髓形成中的重要作用，IRF是IRF转录因子家族的一员。在小鼠模型中，IRF-8基因的改变清楚地阐明了其对骨髓形成的影响。IRF-8缺乏导致骨髓增生性疾病。总之，这些发现表明IRF-8的缺失或下调对骨髓单核细胞的发育和分化具有深远的病理影响。因此，本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的发展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。基于我们肿瘤模型的新初步数据，我们已经确定了丰富水平的G-CSF作为MDSC产生的推定肿瘤衍生因子。因此，G-CSF或其他stat3激活细胞因子诱导的肿瘤诱导的IRF-8下调可能是MDSC发展的新途径。根据我们最近发表的数据，IRF-8水平在肿瘤诱导的MDSC的产生中强烈降低，并与之呈负相关，我们将通过在小鼠模型中追求三个特定目标来验证中心假设：两个将是机制的，一个将是治疗性的：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下调和由此产生的MDSC的肿瘤诱导机制；3)通过IRF-8过表达阻断MDSC发育是否会提高免疫治疗效果。拟议的研究将增强对宿主-肿瘤相互作用的认识，从而为探索这一新的分子途径元素在癌症临床环境中的预后或治疗意义提供框架。

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.