Group 1 Innate Lymphoid Cell Dysregulation in Acute Myeloid Leukemia

项目摘要/摘要 急性髓系白血病(AML)是一种常见的侵袭性血液系统恶性肿瘤，由一种病理类型的 未成熟的髓系细胞扩张。尽管跨越50年的重大研究努力，5年的存活率 急性髓细胞白血病的发病率相对保持不变，为27.4%，强调了创新方法的必要性 治疗。自然杀伤(NK)细胞是第一组先天淋巴样细胞(ILC)家族的成员，它发挥着 在检测和消除白血病细胞方面起着关键作用。然而，我们和其他人之前已经展示了 AML能够抑制NK细胞成熟，促进疾病进展。从机制上讲，我们已经展示了 AML细胞能够分泌芳香烃受体(AHR)转录因子的激动剂， 抑制NK细胞的成熟和功能。越来越多的证据表明，AHR对于 维护一个相关的组1 ILC子集，该子集被称为“ILC1”。值得注意的是，ILC1已被证明是亲- 实体瘤小鼠模型的致瘤作用。因此，我们假设AML能够扭曲ILC人群 抑制NK细胞的免疫监视，促进ILC1s的产生。来自我们小组支持的初步数据 这一假说证明了AML能够以组织特异性的方式扩大ILC1群体 在急性髓系白血病小鼠模型中。此外，我们预测这些ILC1在功能上处于过度活跃的状态 急性髓系白血病和促进疾病进展。我们在这个项目中的长期目标是确定AML如何导致 1组ILCs的调节失调，并阐明其下游对AML进展的影响。因此，我们的 目的是1)确定和描述促进急性髓系白血病IL1扩大的机制(S)和2) 确定急性髓系白血病扩大的ILC1人群的功能后果。为了达到这些目标，我们将 采用体外和体内研究相结合的方法。首先，我们将确定AML是否促进ILC1的扩张 通过NK细胞的相互转换，ILC祖细胞向ILC1表型倾斜，和/或从直接 ILC1s的增殖。我们还将使用转基因小鼠模型来评估AhR和ILC1- 衍生细胞因子在促进AML进展中的作用。通过确定这些机制，我们将能够更好地 靶向这些途径以恢复组1 ILC的动态平衡，并为未来免疫基础研究的发展提供信息 治疗。该项目代表了AML靶向治疗的一种新颖和创新的方法，其重点是 白血病如何针对ILC人群，这是一个迄今为止研究不足的领域。成功完成 这些研究将填补关于急性髓细胞白血病中ILC是如何失调以及这些细胞是如何被调节的关键知识空白 有针对性地治疗以提高患者的存活率。

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a common and aggressive hematologic malignancy caused by a pathologic expansion of immature myeloid cells. Despite significant research efforts spanning 50 years, the 5-year survival rate in AML has remain relatively unchanged at <27.4%, underscoring the need for innovative approaches to treatment. Natural killer (NK) cells are a member of the group 1 innate lymphoid cell (ILC) family that play a pivotal role in the detection and elimination of leukemic cells. However, we and others have previously shown that AML is able to inhibit NK cell maturation, promoting disease progression. Mechanistically, we have shown that AML blasts are capable of secreting agonists for the aryl hydrocarbon receptor (AHR) transcription factor, which inhibits NK cell maturation and function. Accumulating evidence suggests that AHR is required for the maintenance of a related group 1 ILC subset termed an “ILC1.” Notably, ILC1s have been shown to be pro- tumorigenic in solid tumor mouse models. Therefore, we hypothesize that AML is able to skew ILC populations to suppress immune-surveillance by NK cells while promoting ILC1s. Preliminary data from our group support this hypothesis by demonstrating that AML is capable of expanding ILC1 populations in a tissue-specific manner in an AML mouse model. Furthermore, we predict that these ILC1s are functionally hyperactive in the setting of AML and promote disease progression. Our long-term goal in this project is to determine how AML leads to dysregulation of group 1 ILCs and to elucidate the downstream consequences on AML progression. Thus, our aims are 1) to identify and characterize the mechanism(s) which promote ILC1 expansion in AML and 2) to determine the functional consequences of expanded ILC1 populations in AML. To address these aims, we will use a combination of ex vivo and in vivo studies. First, we will determine whether AML promotes ILC1 expansion through interconversion from NK cells, skewing of ILC progenitors towards an ILC1 phenotype, and/or from direct proliferation of ILC1s. We will also use transgenic mouse models to assess the contribution of Ahr and ILC1- derived cytokines in promoting AML progression. By identifying these mechanisms, we will be able to better target these pathways to restore group 1 ILC homeostasis and inform the development of future immune-based therapies. This project represents a novel and innovative approach to targeted therapy in AML by focusing on how leukemia targets ILC populations, an area which has been understudied to date. Successful completion of these studies will fill in critical knowledge gaps of how ILCs are dysregulated in AML and how these cells can be targeted therapeutically to improve patient survival.