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: 10477431
• 负责人: Bethany Mundy-Bosse
• 金额: $ 49.95万
• 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/10477431
• 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; 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.

项目摘要 我们的建议调查了一种急性髓样白血病（AML）的先天免疫功能障碍的机制， 在美国，与白血病相关死亡的主要原因自然是为了防御 恶性肿瘤，但是AML逃避了免疫监视以推动疾病进展。天然杀手（NK）细胞是 负责抗肿瘤免疫监测的主要先天淋巴样细胞（ILC）和NK细胞降低 从头AML和移植后环境中的功能都与结果不佳相关。我们有 最近发现，AML患者在NK细胞发育中遇到基本缺陷，导致特定 NK细胞的亚群的耗竭在协调先天和适应性免疫中的关键作用 响应以及成熟的NK细胞开发和功能。 我们已经表明，NK细胞是由常见的先天淋巴样细胞前体（ILCP）出现的，该细胞生成 一系列NK发育中间体（NKDIS）导致成熟的细胞毒性NK细胞。 ILCP也会产生 对于ILC家族的其他成员，一个非毒性，细胞因子产生的“助手” ILC的潜水员群体 已知是促肿瘤的。我们的初步研究表明，AML破坏了NK谱系，转移 向助手ILC的生产。由于这些人群全部源于ILCP，这表明AML正在作用 ILCP改变血统命运规范。谱系规范是通过精心控制的活动进行的 转录因子改变表观基因组景观产生稳定的细胞类型基因表达 模式。我们的初步研究发现了一个异常，辅助ILC样的DNA甲基化特征 从AML患者和白血病细胞共培养后分离的NKDIS。一个关键的转录因子是芳基 碳氢化合物受体（AHR），我们发现，在AHR配体存在下，助手ILC/NK比率移动 异位由AML细胞产生。我们提出了一种策略，其中AHR抑制和 低甲基化剂（HMAS）指导发育恢复与ILCP的NK细胞分化。 在此提案中，我们将确定AML如何推动这一命运决定并促进助手ILC的产生 通过对从正常供体和AML分离的ILCP进行详细的表观遗传和功能分析 患者，包括投资免疫能力的鼠AML模型。我们将调查功能和 谱系命运的表观遗传中毒，包括AHR的作用。其次，我们将确定 AML患者进行表观遗传程序和疾病进展的NK细胞缺陷，并直接测试影响 ILCP和NKDI开发的HMA。我们还将确定组合两个HMA的临床前效率 以及一种新型的AHR抑制剂，以恢复正常的NK细胞表观遗传编程并增强NK细胞的产生 改善AML临床前模型的结果。维持功能成熟的NK细胞并支持 免疫监护对于长期疾病控制至关重要，这些研究旨在使人们对 AML如何逃避先天免疫学并研究恢复抗肿瘤免疫监视患者的策略。