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

在不同的癌症中，骨髓生成的改变是肿瘤进展的公认表现 类型，包括乳腺癌。这在一定程度上是由于与疾病相关的慢性炎症状态。 进程。这种髓系反应改变的一个主要结果是产生髓系来源的抑制因子。 细胞(MDSCs)。骨髓间充质干细胞由未成熟的髓系细胞组成，反映单核细胞和粒细胞。 来源，这是高度免疫抑制，因此成为各种治疗效果的障碍，以及 尤其是免疫疗法。因此，努力了解MDSC是如何发展或发挥作用的 新策略的发现阻止了它们作为抗肿瘤免疫的负面调节因子的作用。虽然有很多 知道MDSC是如何执行其功能的，但更少知道它们是如何开发或获得 如此压抑的行为。为此，我们实验室之前的工作已经确定了 髓系依赖的转录因子干扰素调节因子-8(IRF8)作为MDSC的负调控因子 制作。通过分泌肿瘤来源的骨髓细胞生长因子，我们发现肿瘤抑制 IRF8在骨髓祖细胞中的表达，导致MDSCs的产生。IRF8的一个因果作用是 通过体内概念验证IRF8基因功能丧失或获得研究证明。此外， 通过这种功能获得途径在髓系中过表达IRF8可降低MDSC 并提高了基于免疫检查点抑制物(ICI)的治疗效果。这些数据表明 IRF8途径可以作为可用药的靶点，而旨在维持髓系IRF8水平的策略可以 减轻MDSC的负担，以提高对免疫疗法的反应。实现该翻译目标的一种方法 是确定积极调控IRF8表达的事件。有趣的是，最近的研究报告了一部小说 Wnt/β-连环蛋白通路在MDSCs调控中的作用与IRF8一样，Wnt/β-catenin似乎是一种 MDSC生成的负调节因子。然而，它们之间的分子和功能关系 有两个监管要素仍然未知。因此，我们假设irf8受Wnt/β-catenin调控。 针对这一轴的信号和策略将增强对ICIS的抗肿瘤反应。重要的是 靶向Wnt/β-连环蛋白信号转导的介入剂是已知的。我们支持这种互动的理由是 基于其他揭示WNT/β-连环蛋白相关转录因子结合位点的其他数据 在irf8和我们的初步数据中显示了Wnt/β-catenin和irf8的协调表达，这 MDSC相对于对照组的下降。为了验证这一假设，我们在小鼠模型中提出了两个目的 乳腺癌：1)证明IRF8的表达受Wnt/β-Catenin依赖的机制的调节 2)检测是否通过遗传或药物作用增强Wnt/β-catenin信号转导 方法增强了ICI的响应性。总而言之，这些研究有可能揭示一部小说 Wnt/β-catenin-IRF8轴在骨髓间充质干细胞生物学中的作用，为改善脑梗塞的疗效提供了一条治疗途径。

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.