Dysregulation of Innate Lymphoid Immunity in Acute Myeloid Leukemia

急性髓系白血病先天性淋巴免疫失调

• 批准号: 10299223
• 负责人: Bethany Mundy-Bosse
• 金额: $ 51.44万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299223
• 关键词: Aberrant DNA Methylation; Acute Myelocytic Leukemia; Address; Aryl Hydrocarbon Receptor; Automobile Driving; CD34 gene; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Cellular biology; Cessation of life; Coculture Techniques; DNA Methylation; Data; Defect; Detection; Development; Disease; Disease Progression; Environment; Epigenetic Process; Equilibrium; Evaluation; Family; Gene Expression Profile; Generations; Hematologic Neoplasms; Hematopoietic stem cells; Homeostasis; Immune; Immune Evasion; Immune System Diseases; Immune system; Immunity; Immunocompetent; Immunologic Surveillance; Immunotherapeutic agent; In Vitro; Individual; Innate Immune Response; Innate Immune System; Investigation; Leukemic Cell; Lymphoid; Lymphoid Cell; Maintenance; Malignant Neoplasms; Maps; Modeling; Molecular; Mus; Natural Immunity; Natural Killer Cells; Outcome; Pathway interactions; Patients; Play; Population; Pre-Clinical Model; Process; Production; Public Health; Receptor Activation; Receptor Inhibition; Regulation; Relapse; Role; Sampling; Series; Survival Rate; System; Testing; Treatment Efficacy; acute myeloid leukemia cell; adaptive immune response; aryl hydrocarbon receptor ligand; cancer cell; cell type; cytokine; cytotoxic; disorder control; epigenetic regulation; epigenome; epigenomics; genome-wide; immune activation; improved; improved outcome; in vivo Model; inhibitor/antagonist; innate immune mechanisms; leukemia; member; methylation pattern; novel; novel strategies; novel therapeutics; post-transplant; preclinical efficacy; prevent; programs; response; restoration; stem; transcription factor; tumor; tumorigenic

PROJECT SUMMARY Our proposal investigates a mechanism underlying innate immune dysfunction in acute myeloid leukemia (AML), the leading cause of leukemia-related deaths in the U.S. The innate immune system naturally defends against malignancy, however AML evades immunosurveillance to drive disease progression. Natural killer (NK) cells are the primarily innate lymphoid cell (ILC) responsible for anti-tumor immune surveillance, and reduced NK cell function both in de novo AML and in the post-transplant setting is correlated with poor outcomes. We have recently discovered that AML patients carry a fundamental defect in NK cell development leading to specific depletion of a sub-population of NK cells with critical roles in coordinating innate and adaptive immune responses, as well as mature NK cell development and function. We have shown that NK cells develop from a common innate lymphoid cell precursor (ILCP), which generates a series of NK developmental intermediates (NKDIs) leading to mature, cytotoxic NK cells. ILCPs also give rise to the other members of the ILC family, a diverse group of non-cytotoxic, cytokine-producing “helper” ILCs that are known to be pro-tumorigenic. Our preliminary studies show that AML disrupts the NK lineage, shifting production towards helper ILCs. As these populations all stem from the ILCP, this suggests AML is acting on ILCPs to alter lineage fate specification. Lineage specification occurs through carefully controlled activities of transcription factors that modify the epigenomic landscape generating stable cell type-specific gene expression patterns. Our preliminary studies have uncovered an aberrant, helper ILC-like DNA methylation signature in NKDIs isolated from AML patients and following leukemic cell co-culture. One key transcription factor is the aryl hydrocarbon receptor (AHR), which we have found shifts the helper ILC/NK ratio in the presence of AHR ligands ectopic produced by AML cells. We propose a strategy where the combination of AHR inhibition and hypomethylating agents (HMAs) guides development to restore NK cell differentiation from the ILCP. In this proposal, we will determine how AML drives this fate decision and promotes the generation of helper ILCs by performing detailed epigenetic and functional analyses of ILCPs isolated from normal donors and AML patients, including investigation in an immunocompetent murine AML model. We will investigate functional and epigenetic poising of lineage fate including the role of AHR. Secondly, we will determine the relationship of the NK cell defect in AML patients to epigenetic programming and disease progression, and directly test the impact of HMAs on ILCP and NKDI development. We will also determine the preclinical efficacy of combining both HMA and a novel AHR inhibitor to restore normal NK cell epigenetic programming and enhance NK cell generation to improve outcomes in preclinical models of AML. Maintaining functionally mature NK cells and supporting immunosurveillance is critical to long-term disease control, these studies aim to gain a novel understanding of how AML evades innate immunity and investigate strategies to restore anti-tumor immune surveillance patients.

项目总结 我们的建议是研究急性髓系白血病(AML)先天免疫功能障碍的机制。 美国白血病相关死亡的主要原因先天免疫系统天然防御 恶性，然而，急性髓细胞白血病逃避免疫监视，以推动疾病进展。自然杀伤(NK)细胞是 主要是先天淋巴样细胞(ILC)负责抗肿瘤免疫监测，并减少NK细胞 无论是在初治AML中还是在移植后环境中，功能都与不良预后相关。我们有 最近发现AML患者在NK细胞发育方面存在根本性缺陷，导致特定的 在协调天然免疫和获得性免疫中起关键作用的NK细胞亚群的耗尽 反应，以及成熟的NK细胞的发育和功能。 我们已经证明，NK细胞是从一种常见的先天淋巴样细胞前体(ILCP)发展而来的，它可以产生 一系列NK发育中间产物(NKDIs)，可导致成熟的、具有细胞毒性的NK细胞。ILCP也会导致 对于ILC家族的其他成员，一组不同的非细胞毒性、产生细胞因子的“辅助”ILC 都是已知的促肿瘤物质。我们的初步研究表明，AML扰乱了NK血统，改变了 向帮助者国际劳工组织提供生产。由于这些群体都来自iLCP，这表明AML正在作用于 ILCP改变血统命运规范。血统规范通过仔细控制的活动进行 改变表观基因组图谱的转录因子，产生稳定的细胞类型特异性基因表达 模式。我们的初步研究发现了一种异常的、辅助性ILC样DNA甲基化签名 NKDIs是从AML患者和白血病细胞共培养后分离出来的。一个关键的转录因子是芳基 我们已经发现的碳氢受体(AHR)在AHR配体存在的情况下改变辅助细胞ILC/NK的比率 急性髓系白血病细胞产生的异位。我们提出了一种策略，将AHR抑制和 去甲基化药物(HMAS)指导发育以恢复iLCP对NK细胞的分化。 在这项提案中，我们将确定AML如何推动这一命运决定，并促进辅助ILC的产生 通过对从正常供者和AML分离的ILCP进行详细的表观遗传学和功能分析 患者，包括在具有免疫能力的小鼠急性髓细胞白血病模型中的研究。我们将调查功能性和 血统命运的表观遗传平衡，包括AHR的作用。其次，我们将确定两国之间的关系 NK细胞缺陷对AML患者表观遗传编程和疾病进展的影响 关于iLCP和NKDI开发的HMAS。我们还将确定联合两种HMA的临床前疗效。 和一种新的AHR抑制剂，以恢复正常的NK细胞表观遗传编程，并促进NK细胞的生成 改善急性髓系白血病临床前模型的结果。维持功能成熟的NK细胞并支持 免疫监测对长期疾病控制至关重要，这些研究旨在获得对 AML如何逃避天然免疫，并研究恢复抗肿瘤免疫监测患者的策略。