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

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.

项目概要/摘要急性髓系白血病（AML）是最常见的成人白血病，预后极差；最多被诊断患有 AML 的患者将死于这种疾病。 AML是由不良细胞不受控制的增殖造成的分化的骨髓前体细胞。免疫疗法，包括检查点封锁，目前正在研究中在 AML 背景下进行研究。我们之前的工作已经确定 T 细胞的百分比存在于 AML 患者诊断时的骨髓与总生存率相关，这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研究表明，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，这种功能抑制可以通过免疫检查点分子阻断在体外逆转。先前的文献表明，免疫系统的疲惫状态可能是由于慢性刺激后赋予 T 细胞的表观遗传程序。我们之前已经展示过地图的角色激酶通路 (MAPK) 维持 AML 中 T 细胞的这种耗尽状态。将细胞转化为 AML 是影响增殖、分化和表观遗传状态的突变组合的结果。为了这因此，针对信号传导和表观遗传状态的药物已被批准或正在积极研究 AML 的治疗。对于这个项目，我们的长期目标是更好地了解功能性 T 细胞耗竭及其在 AML 中的相关性。我们的近期目标是研究 MAPK 途径、DNA 甲基转移酶的作用以及 AML 背景下 T 细胞耗竭中的表观遗传阅读器 BET 蛋白。我们将进行这些研究核心假设是 AML 中通过 T 细胞耗竭的免疫逃避是由信号通路传递的例如 T 细胞中的 MEK 和表观遗传状态，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) 理解 MAPK 的作用 AML 中 T 细胞功能的通路。这将包括 T 细胞的机制研究，同时也研究肿瘤和 AML 免疫微环境中的其他淋巴和骨髓细胞群。 2) 评估影响表观遗传途径对 AML 小鼠模型中 T 细胞免疫功能的影响。根据我们的初步数据我们将重点关注 DNA 甲基化和 BET 蛋白质功能。 3）定义免疫细胞和途径人类 AML 肿瘤微环境的抑制。我们将研究与 T 细胞相关的细胞类型患者样本中的抑制。我们还将研究 MEK、BET 和 DNMT 抑制剂对患者样本的影响。这些实验将使我们更好地了解 AML 中 T 细胞耗竭的生物学原理疾病。重要的是，这些研究的结果将通过允许对这种致命疾病的治疗产生影响合理设计小分子与免疫靶向联合疗法。