Pathways of Immune Evasion in Acute Myeloid Leukemia

急性髓系白血病的免疫逃避途径

基本信息

批准号：
10594502
负责人：
Evan Ferguson Lind
金额：
$ 34.26万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-18 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594502
关键词：
Acute Myelocytic Leukemia Adaptive Immune System Affect Amino Acid Motifs Animal Model Antibodies Behavior Biology Blood Bone Marrow Bone Marrow Aspiration Bromodomain Bromodomains and extra-terminal domain inhibitor Cell Differentiation process Cell Survival Cell physiology Cells Cessation of life Chromatin Chromatin Structure Chronic DNA Methylation DNA Methyltransferase Inhibitor DNA Modification Methylases Data Development Diagnosis Disease Drug Targeting Drug usage Epigenetic Process Family member Functional disorder Future Genetic Transcription Genetically Engineered Mouse Goals Hematopoietic Neoplasms Human Immune Immune Evasion Immune Targeting Immune system Immunosuppression Immunotherapy Impairment In Vitro Laboratories Leukemic Cell Literature Lymphoid MEK inhibition MEKs Malignant Neoplasms Mitogen-Activated Protein Kinases Mutation Myelogenous Pathway interactions Patients Pharmaceutical Preparations Phenotype Population Prognosis Proliferating Property Protein Methyltransferases Publishing Reader Role Sampling Signal Pathway Signal Transduction T cell regulation T-Cell Depletion T-Cell Proliferation T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Time Tumor Escape Work adult leukemia cancer cell cancer type cell transformation cell type cytokine epigenome exhaust exhaustion experimental study functional disability immune checkpoint immune checkpoint blockade immune clearance immune function improved in vivo inhibitor leukemia mouse model neoplastic cell novel precursor cell programs protein function rational design response small molecule targeted treatment transcription factor tumor tumor microenvironment tumor-immune system interactions

Acute Myelocytic Leukemia Adaptive Immune System Affect Amino Acid Motifs Animal Model Antibodies Behavior Biology Blood Bone Marrow Bone Marrow Aspiration Bromodomain Bromodomains and extra-terminal domain inhibitor Cell Differentiation process Cell Survival Cell physiology Cells Cessation of life Chromatin Chromatin Structure Chronic DNA Methylation DNA Methyltransferase Inhibitor DNA Modification Methylases Data Development Diagnosis Disease Drug Targeting Drug usage Epigenetic Process Family member Functional disorder Future Genetic Transcription Genetically Engineered Mouse Goals Hematopoietic Neoplasms Human Immune Immune Evasion Immune Targeting Immune system Immunosuppression Immunotherapy Impairment In Vitro Laboratories Leukemic Cell Literature Lymphoid MEK inhibition MEKs Malignant Neoplasms Mitogen-Activated Protein Kinases Mutation Myelogenous Pathway interactions Patients Pharmaceutical Preparations Phenotype Population Prognosis Proliferating Property Protein Methyltransferases Publishing Reader Role Sampling Signal Pathway Signal Transduction T cell regulation T-Cell Depletion T-Cell Proliferation T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Time Tumor Escape Work adult leukemia cancer cell cancer type cell transformation cell type cytokine epigenome exhaust exhaustion experimental study functional disability immune checkpoint immune checkpoint blockade immune clearance immune function improved in vivo inhibitor leukemia mouse model neoplastic cell novel precursor cell programs protein function rational design response small molecule targeted treatment transcription factor tumor tumor microenvironment tumor-immune system interactions

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项目摘要

Project Summary/Abstract Acute Myeloid Leukemia (AML) is the most common adult leukemia and has a very poor prognosis; most patients diagnosed with AML will die from this disease. AML results from uncontrolled proliferation of poorly differentiated myeloid precursor cells. Immune therapies, including checkpoint blockade, are currently being studied in the context of AML. Our previous work has established that the percentage of T cells present in the bone marrow of patients with AML at the time of diagnosis correlates with overall survival, providing evidence that the adaptive immune system, and specifically T cells, are able to recognize malignant cells. Our lab and others have shown that AML evades attack by the immune system by suppressing T cell function. Significantly, this functional suppression can be reversed in vitro in most cases by immune checkpoint molecule blockade. Previous literature has demonstrated that the exhausted state of the immune system can result from an epigenetic program imparted on T cells after chronic stimulation. We have previously shown a role for the map kinase pathway (MAPK) in maintaining this exhausted state in T cells present in AML. Transformation of cells to AML results from a combination of mutations affecting proliferation, differentiation and epigenetic state. For this reason, drugs targeting signaling and epigenetic state are approved or are being actively studied for the treatment of AML. For this project, our long-term goals are to provide a better understanding of functional T cell exhaustion and its relevance in AML. Our immediate goal is to study the role of the MAPK pathway, DNA methyltransferases and the epigenetic reader BET proteins in T cell exhaustion in the context of AML. We will conduct these studies with the central hypothesis that immune evasion via T cell exhaustion in AML is imparted by signaling pathways such as MEK and epigenetic states in T cells and that targeting these pathways in AML will reverse immune suppression. To accomplish this goal, we propose the following three aims: 1) Understand the role of the MAPK pathway on T cell function in AML. This will consist of mechanistic studies in T cells, but also study tumor and other lymphoid and myeloid populations in the immune microenvironment of AML. 2) Assess the impact of epigenetic pathways on the immunological function of T cells in mouse models of AML. Based on our preliminary data we will focus on DNA methylation and BET protein function. 3) Define cells and pathways of immune suppression in the tumor microenvironment of human AML. We will study a cell type associated with T cell suppression in patient samples. We will also study effects of MEK, BET and DNMT inhibitors on patient samples. Together these experiments will give us a better understanding of the biology of T cell exhaustion in AML disease. Importantly, results from these studies will have impact on treatment of this lethal disease by allowing rational design of combined small molecule and immune targeted therapies.

项目摘要/摘要急性髓样白血病（AML）是最常见的成年白血病，预后较差。最多被诊断为AML的患者将死于这种疾病。 AML是由于不受控制的不良增殖而产生的分化的髓样前体细胞。免疫疗法，包括检查点封锁，目前正在在AML的背景下进行了研究。我们以前的工作已经确定，T细胞中存在的T细胞的百分比诊断时AML患者的骨髓与整体生存相关，提供了证据适应性免疫系统，特别是T细胞能够识别恶性细胞。我们的实验室和其他人则表明，AML通过抑制T细胞功能来逃避免疫系统的攻击。显著地，在大多数情况下，可以通过免疫检查点分子阻断来在体外逆转这种功能抑制。以前的文献表明，免疫系统的疲惫状态可能是由慢性刺激后，表观遗传程序赋予T细胞。我们以前已经显示了地图的作用激酶途径（MAPK）在AML中存在的T细胞中保持这种耗尽的状态。细胞转化 AML是由影响增殖，分化和表观遗传状态的突变组合的。为了这原因，批准靶向信号传导和表观遗传状态的药物或正在积极研究 AML的处理。对于这个项目，我们的长期目标是更好地了解功能性T细胞耗尽及其在AML中的相关性。我们的直接目标是研究MAPK途径，DNA甲基转移酶的作用在AML的背景下，表观遗传学读取器在T细胞耗尽中下注蛋白。我们将进行这些研究通过信号通路来赋予AML中通过T细胞耗尽的免疫逃避的中心假设例如T细胞中的MEK和表观遗传态，并且针对AML中的这些途径将逆转免疫抑制。为了实现这一目标，我们提出以下三个目标：1）了解MAPK的作用 AML中T细胞功能的途径。这将包括在T细胞中的机械研究，但也研究肿瘤和 AML免疫微环境中的其他淋巴样和髓样群。 2）评估 AML小鼠模型中T细胞免疫功能的表观遗传途径。基于我们的初步数据我们将重点放在DNA甲基化和BET蛋白功能上。 3）定义免疫的细胞和途径在人AML的肿瘤微环境中抑制。我们将研究与T细胞相关的细胞类型抑制患者样品。我们还将研究MEK，BET和DNMT抑制剂对患者样品的影响。这些实验将使我们更好地了解AML中T细胞耗尽的生物学疾病。重要的是，这些研究的结果将对这种致命疾病的治疗产生影响合并的小分子和免疫靶向疗法的合理设计。