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: 10689202
• 负责人: Bethany Mundy-Bosse
• 金额: $ 49.67万
• 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/10689202
• 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; Immunophenotyping; Immunotherapeutic agent; In Vitro; Individual; Innate Immune Response; Innate Immune System; Investigation; Leukemic Cell; Leukemic Natural Killer Cell; Lymphocyte; Lymphoid; Lymphoid Cell; Maintenance; Malignant Neoplasms; Maps; Modeling; Molecular; Mus; Natural Immunity; Natural Killer Cells; Outcome; Pathway interactions; Patients; Population; Pre-Clinical Model; Precursor Natural Killer Cell; Process; Production; Public Health; Receptor Activation; Receptor Inhibition; Regulation; Role; Sampling; Series; Specific qualifier value; Survival Rate; System; Testing; Treatment Efficacy; United States; 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; relapse prevention; response; restoration; stem; targeted treatment; 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.

项目概要 我们的提案研究了急性髓系白血病（AML）先天免疫功能障碍的潜在机制， 在美国，白血病相关死亡的主要原因是先天免疫系统自然地防御 然而，AML 会逃避免疫监视来驱动疾病进展。 负责抗肿瘤免疫监视的主要先天淋巴细胞 (ILC)，以及减少的 NK 细胞 我们发现，新发 AML 和移植后的功能都与不良结果相关。 最近发现 AML 患者的 NK 细胞发育存在根本缺陷，导致特定的 消耗在协调先天性和适应性免疫中发挥关键作用的 NK 细胞亚群 反应以及成熟 NK 细胞的发育和功能。 我们已经证明 NK 细胞是由共同的先天性淋巴细胞前体细胞 (ILCP) 发育而来，可产生 一系列导致成熟、细胞毒性 NK 细胞的 NK 发育中间体 (NKDI) 也会产生。 对于 ILC 家族的其他成员来说，这是一组不同的非细胞毒性、产生细胞因子的“辅助”ILC， 我们的初步研究表明，AML 会破坏 NK 谱系，从而发生转变。 由于这些群体均源自 ILCP，这表明 AML 正在作用于生产辅助 ILC。 ILCP 改变谱系命运规范 谱系规范是通过仔细控制的活动而发生的。 改变表观基因组景观的转录因子产生稳定的细胞类型特异性基因表达 我们的初步研究发现了异常的、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 NKDI 之一关键转录因子是芳基。 碳氢化合物受体 (AHR)，我们发现在 AHR 配体存在的情况下，它会改变辅助 ILC/NK 比率 我们提出了一种将 AHR 抑制和抑制相结合的策略。 去甲基化剂 (HMA) 指导发育以恢复 NK 细胞从 ILCP 的分化。 在本提案中，我们将确定 AML 如何推动这一命运决定并促进辅助 ILC 的生成 通过对从正常供体和 AML 中分离的 ILCP 进行详细的表观遗传学和功能分析 患者，包括免疫活性小鼠 AML 模型的研究，我们将研究功能和功能。 其次，我们将确定谱系命运的表观遗传平衡，包括 AHR 的作用。 AML患者的NK细胞缺陷对表观遗传编程和疾病进展的影响，并直接测试 我们还将确定 HMA 对 ILCP 和 NKDI 开发的临床前疗效。 以及一种新型 AHR 抑制剂，可恢复正常 NK 细胞表观遗传编程并增强 NK 细胞生成 改善 AML 临床前模型的结果，维持功能成熟的 NK 细胞并支持 免疫监视对于长期疾病控制至关重要，这些研究旨在获得对 AML 如何逃避先天免疫并研究恢复患者抗肿瘤免疫监视的策略。