Group 1 Innate Lymphoid Cell Dysregulation in Acute Myeloid Leukemia

第 1 组：急性髓系白血病的先天淋巴细胞失调

• 批准号: 10547763
• 负责人: Matthew Lordo
• 金额: $ 4.29万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-03 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10547763
• 关键词: Acute Myelocytic Leukemia; Address; Adoptive Transfer; Affect; Agonist; Area; Aryl Hydrocarbon Receptor; Biological Assay; Biology; Cell Line; Cell Lineage; Cell Maturation; Cell physiology; Clinical; Clinical Research; Coculture Techniques; Data; Defect; Detection; Development; Disease; Disease Progression; Family; Future; Genes; Goals; Growth; Hematologic Neoplasms; Homeostasis; Human; Hyperactivity; Immune; Immune Evasion; Immunologic Surveillance; Immunotherapy; Interleukin-2; Knockout Mice; Knowledge; Label; Leukemic Cell; Ligands; Lymphoid Cell; Maintenance; Malignant - descriptor; Malignant Neoplasms; Measures; Modeling; Mus; Myeloid Cells; Natural Killer Cells; Outcome; Pathologic; Pathway interactions; Patients; Phenotype; Play; Population; Proliferating; Publishing; Receptor Activation; Receptor Inhibition; Receptor Signaling; Regulatory T-Lymphocyte; Relapse; Research; Role; Solid Neoplasm; Support Groups; Survival Rate; T-Cell Development; T-Cell Proliferation; Testing; Therapeutic; Tissues; Transgenic Mice; Treatment Efficacy; acute myeloid leukemia cell; aryl hydrocarbon receptor ligand; cancer cell; cell type; conditional knockout; cytokine; cytotoxic; design; improved; in vivo; inhibitor; innovation; leukemia; member; mouse model; novel; older patient; patient derived xenograft model; pharmacologic; stem cells; targeted treatment; transcription factor; tumorigenic

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.

项目摘要/摘要 急性髓样白血病（AML）是由病理引起的常见和侵略性血液学恶性肿瘤 未成熟的髓样细胞的膨胀。尽管跨越了50年的重大研究工作，但5年生存 AML的速率在<27.4％的情况下保持相对不变，强调了对创新方法的需求 治疗。天然杀手（NK）细胞是1组先天淋巴样细胞（ILC）家族的成员 在检测和消除白血病细胞中的关键作用。但是，我们和其他人以前已经显示 该AML能够抑制NK细胞的成熟，从而促进疾病进展。从机械上讲，我们已经显示 AML爆炸能够为芳基烃受体（AHR）转录因子分泌激动剂， 抑制NK细胞的成熟和功能。积累的证据表明，AHR是必需的 相关组1 ILC子集的维护称为“ ILC1”。值得注意的是，ILC1已被证明是对的 实体肿瘤小鼠模型中的肿瘤毒素。因此，我们假设AML能够偏向ILC种群 在促进ILC1时，NK细胞抑制免疫监测。来自我们小组支持的初步数据 通过证明AML能够以组织特异性的方式扩展ILC1种群，这一假设 在AML鼠标模型中。此外，我们预测，在 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 第1组ILC的失调并阐明了对AML进程的下游后果。那，我们的 目的是1）识别和表征促进AML中ILC1扩展和2）的机制 确定AML中扩展的ILC1种群的功能后果。为了解决这些目标，我们将 结合体内和体内研究。首先，我们将确定AML是否促进ILC1扩展 通过从NK细胞的互连，将ILC祖细胞偏向ILC1表型和/或直接 ILC1的增殖。我们还将使用转基因小鼠模型来评估AHR和ILC1-的贡献 衍生的细胞因子在促进AML进展中。通过识别这些机制，我们将能够更好 针对这些途径来恢复第1组ILC稳态，并告知未来免疫的发展 疗法。该项目代表了一种新颖而创新的AML靶向治疗方法 白血病如何靶向ILC人群，该地区迄今已被理解。成功完成 这些研究将填补有关ILC在AML中如何失调以及这些细胞如何变化的关键知识差距 针对治疗以改善患者的生存率。