The Wnt-IRF8 axis: a Novel Regulator of Myeloid-Derived Suppressor Cell Biology

Wnt-IRF8 轴：骨髓源性抑制细胞生物学的新型调节器

• 批准号: 10208721
• 负责人: Elliot David Kramer
• 金额: $ 3.08万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208721
• 关键词: Antitumor Response; Behavior; Binding; Binding Sites; Biological Response Modifiers; Bone Marrow; Breast Cancer Model; CD8-Positive T-Lymphocytes; Cancer Model; Cancer Patient; Cell Count; Cell physiology; Cells; Cellular biology; Chronic; Clinical; Critical Pathways; Cues; Data; Data Analyses; Data Set; Development; Disease; Down-Regulation; Event; Exhibits; Exposure to; Flow Cytometry; Frequencies; Gene Expression; Gene Expression Profiling; Generations; Genetic; Genetic Transcription; Goals; Growth Factor; IFN consensus sequence binding protein; Image; Immune; Immune Targeting; Immune checkpoint inhibitor; Immunosuppression; Immunotherapy; In Vitro; Inflammatory; Intervention; Knowledge; Laboratories; Malignant Neoplasms; Mediating; Molecular; Monoclonal Antibodies; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Myelopoiesis; Nuclear; Outcome; Pathway interactions; Pharmacology; Population; Process; Production; Promoter Regions; Proteins; Regulation; Regulatory Element; Reporting; Role; Signal Pathway; Signal Transduction; Solid; System; T cell response; Testing; Therapeutic; Therapeutic Intervention; Time; Treatment Efficacy; Tumor Cell Biology; Tumor Immunity; Tumor-Derived; Work; anti-CTLA4; anti-PD-1; base; beta catenin; cancer type; design; druggable target; gain of function; granulocyte; granulocyte-monocyte progenitors; immune checkpoint blockade; improved; in silico; in vivo; inhibitor/antagonist; insight; malignant breast neoplasm; molecular targeted therapies; monocyte; mouse model; neoplastic; new therapeutic target; novel; overexpression; pre-clinical; progenitor; programs; promoter; response; targeted agent; targeted treatment; therapy resistant; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor progression; tumorigenic

Alterations in myelopoiesis are a well-recognized manifestation of tumor progression across different cancer types, including breast cancer. This is due in part to the chronic inflammatory state associated with the disease process. A major outcome of this altered myeloid response is the production of myeloid-derived suppressor cells (MDSCs). MDSCs consist of immature myeloid populations, reflecting cells of monocytic and granulocytic origin, that are highly immune suppressive and thus act as roadblocks to the efficacy of diverse therapies, and immunotherapy in particular. Thus, efforts to understand how MDSCs develop or function are instrumental for the discovery of new strategies that block their role as negative regulators of anti-tumor immunity. While much is known about how MDSCs execute their functions, much less is known about how they develop or acquire such suppressive behavior. To that end, previous work in our laboratory has identified an important role for the myeloid-dependent transcription factor, interferon regulatory factor-8 (IRF8) as a negative regulator of MDSC production. Through the secretion of tumor-derived myelopoietic growth factors, we showed that tumors inhibit IRF8 expression in bone marrow progenitors, leading to the generation of MDSCs. A causal role for IRF8 was demonstrated through in vivo proof-of-concept IRF8 genetic loss- or gain-of-function studies. Moreover, the overexpression of IRF8 in the myeloid system through such gain-of-function approaches reduced MDSC numbers and boosted the efficacy of immune checkpoint inhibitor (ICI)-based therapy. These data suggest that the IRF8 pathway may serve as a druggable target and strategies designed to sustain myeloid IRF8 levels may lessen MDSC burden to boost responses to immunotherapies. One approach to achieve that translational goal is to identify events that positively regulate IRF8 expression. Interestingly, recent studies have reported a novel role for the Wnt/β-catenin pathway in the regulation of MDSCs. As with IRF8, Wnt/β-catenin appears to be a negative regulator of MDSC generation. However, the molecular and functional relationship between these two regulatory elements remain unknown. Thus, we hypothesize that IRF8 is regulated by Wnt/β-catenin signaling and that strategies which target this axis will enhance antitumor responses to ICIs. Importantly, interventional agents that target Wnt/β-catenin signaling are known. Our rationale to support this interaction is based on data elsewhere that reveal putative Wnt/β-catenin-associated transcription factors binding sites within IRF8 and our preliminary data that show coordinated expression of both Wnt/β-catenin and IRF8, which declines in MDSCs relative to the controls. To test this hypothesis, we propose two aims in mouse models of breast cancer: 1) to demonstrate that IRF8 expression is regulated by a Wnt/β-catenin-dependent mechanism to impact MDSCs; and 2) to test whether enhancing Wnt/β-catenin signaling by genetic or pharmacologic approaches enhance ICI responsiveness. Altogether, these studies have the potential to uncover a novel Wnt/β-catenin-IRF8 axis in MDSC biology and offer a therapeutic avenue for improving ICI efficacy.

骨髓生成的改变是不同癌症中肿瘤进展的公认表现 类型，包括乳腺癌。这部分是由于与疾病相关的慢性炎症状态 过程这种改变的髓系反应的一个主要结果是髓源性抑制因子的产生， 细胞（MDSC）。MDSC由未成熟的骨髓细胞群组成，反映单核细胞和粒细胞的细胞分化。 来源，具有高度免疫抑制作用，因此成为各种疗法功效的障碍，以及 尤其是免疫疗法。因此，了解MDSC如何发展或发挥作用的努力有助于 发现阻断其作为抗肿瘤免疫负调节剂的作用的新策略。虽然大部分 关于MDSC如何执行其功能，人们所知甚少，关于它们如何发展或获得 这种压抑的行为。为此，我们实验室以前的工作已经确定了 髓系依赖性转录因子干扰素调节因子-8（IRF 8）作为MDSC的负调节因子 生产通过肿瘤源性骨髓生长因子的分泌，我们发现肿瘤抑制 IRF 8在骨髓祖细胞中的表达，导致MDSC的产生。IRF 8的因果作用是 通过体内概念验证IRF 8遗传功能丧失或获得研究证实。而且 通过这种功能获得方法在骨髓系统中过表达IRF 8减少了MDSC 数字和提高免疫检查点抑制剂（ICI）为基础的治疗的疗效。这些数据表明 IRF 8通路可以作为药物靶点，设计用于维持髓样IRF 8水平的策略可以 减轻MDSC负担，以增强对免疫疗法的反应。实现这一转化目标的一种方法是 是鉴定正调节IRF 8表达的事件。有趣的是，最近的研究报道了一种新的 Wnt/β-catenin通路在MDSC调控中的作用。与IRF 8一样，Wnt/β-连环蛋白似乎是一个 MDSC生成的负调节因子。然而，这些之间的分子和功能关系 有两个调控因素仍然未知。因此，我们假设IRF 8受Wnt/β-catenin调节， 信号传导，靶向该轴的策略将增强对ICI的抗肿瘤反应。重要的是， 靶向Wnt/β-连环蛋白信号传导的干预剂是已知的。我们支持这种互动的理由是 基于其他地方的数据，这些数据揭示了假定的Wnt/β-连环蛋白相关转录因子结合位点 我们的初步数据显示Wnt/β-catenin和IRF 8的协调表达， 相对于对照，MDSC下降。为了验证这一假设，我们提出了两个目标，在小鼠模型中， 乳腺癌：1）证明IRF 8表达受Wnt/β-连环蛋白依赖性机制调节 影响MDSC;和2）测试是否通过遗传或药理学途径增强Wnt/β-连环蛋白信号传导 方法增强ICI响应性。总之，这些研究有可能揭示一种新的 Wnt/β-catenin-IRF 8轴在MDSC生物学中的作用，并为改善ICI疗效提供了治疗途径。