Pathways of Immune Evasion in Acute Myeloid Leukemia

项目摘要/摘要 急性髓系白血病(AML)是最常见的成人白血病，预后非常差；大多数 被诊断为急性髓细胞白血病的患者将死于这种疾病。急性髓系白血病是由恶性疾病的不受控制的扩散引起的 分化的髓系前体细胞。包括封锁检查站在内的免疫疗法目前正在进行中 在反洗钱的背景下进行了研究。我们之前的工作已经确定，T细胞在体内的百分比 AML患者确诊时的骨髓与总存活率相关，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 其他研究表明，AML通过抑制T细胞功能来逃避免疫系统的攻击。值得注意的是， 在大多数情况下，这种功能抑制在体外可以通过免疫检查点分子的阻断而逆转。 以前的文献已经证明，免疫系统的疲惫状态可能是由 T细胞在慢性刺激后的表观遗传程序。我们之前已经展示了地图的角色 在急性髓系白血病T细胞中维持这种耗竭状态的蛋白激酶途径(MAPK)。将细胞转化为 AML是一系列影响增殖、分化和表观遗传状态的突变的结果。为了这个 原因是，靶向信号转导和表观遗传状态的药物已获得批准或正在积极研究 急性髓系白血病的治疗。 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 及其在急性髓系白血病中的相关性。我们的近期目标是研究MAPK通路DNA甲基转移酶的作用 以及AML背景下T细胞衰竭中的表观遗传读物BET蛋白。我们会进行这些研究 中心假说是急性髓细胞白血病通过T细胞耗竭通过信号通路传递免疫逃避 例如T细胞中MEK和表观遗传状态，而在AML中靶向这些途径将逆转免疫 压制。为了实现这一目标，我们提出了以下三个目标：1)理解MAPK的作用 急性髓系白血病中T细胞功能的途径。这将包括T细胞的机制研究，但也包括肿瘤和 AML免疫微环境中的其他淋巴和髓系细胞群。2)评估以下项目的影响 急性髓系白血病小鼠模型T细胞免疫功能的表观遗传途径。根据我们的初步调查 资料我们将重点介绍DNA甲基化和BET蛋白的功能。3)确定免疫的细胞和途径 人急性髓系白血病肿瘤微环境的抑制作用。我们将研究一种与T细胞相关的细胞类型 病人样本中的抑制。我们还将研究MEK、BET和DNMT抑制剂对患者样本的影响。 总之，这些实验将使我们更好地了解急性髓细胞白血病中T细胞耗竭的生物学机制 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 合理设计小分子和免疫靶向联合治疗。

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.