Group 1 Innate Lymphoid Cell Dysregulation in Acute Myeloid Leukemia

项目总结/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， 未成熟骨髓细胞的扩增。尽管50年来进行了大量的研究， AML的发病率保持相对不变，<27.4%，强调需要创新方法， 治疗自然杀伤（NK）细胞是第1组先天性淋巴样细胞（ILC）家族的成员， 在检测和清除白血病细胞中起关键作用。然而，我们和其他人之前已经证明， AML能够抑制NK细胞成熟，促进疾病进展。从机制上讲，我们已经证明 AML母细胞能够分泌芳香烃受体（AHR）转录因子的激动剂， 其抑制NK细胞成熟和功能。越来越多的证据表明， 维持称为“ILC 1”的相关第1组ILC子集。值得注意的是，ILC 1已被证明是亲- 在实体瘤小鼠模型中的致瘤性。因此，我们假设AML能够使ILC人群发生倾斜， 抑制NK细胞的免疫监视，同时促进ILC 1。来自我们团队支持的初步数据 通过证明AML能够以组织特异性方式扩增ILC 1群体， 在AML小鼠模型中。此外，我们预测，这些ILC 1是功能亢进的设置， AML并促进疾病进展。我们在这个项目中的长期目标是确定AML如何导致 研究组1 ILC的失调，并阐明AML进展的下游后果。所以我们 目的是1）确定和描述促进AML中ILC 1扩展的机制，2） 确定AML中扩增的ILC 1群体的功能后果。为了实现这些目标，我们将 使用离体和体内研究的组合。首先，我们将确定AML是否促进ILC 1扩增 通过与NK细胞的相互转化，ILC祖细胞向ILC 1表型的倾斜，和/或与直接转化的相互转化， ILC 1的增殖。我们还将使用转基因小鼠模型来评估Ahr和ILC 1的贡献。 衍生的细胞因子促进AML进展。通过识别这些机制，我们将能够更好地 靶向这些途径，以恢复第1组ILC的稳态，并为未来基于免疫的 治疗该项目代表了AML靶向治疗的一种新的创新方法， 白血病如何靶向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AML中ILC如何失调以及这些细胞如何在AML中表达的关键知识空白。 以提高患者的生存率。

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.