Minor Histocompatibility Antigen T Cell Targeting in Acute Myeloid Leukemia

项目摘要/摘要 急性髓系白血病(AML)是一种流行的致命癌症，预计新增病例为20,000人，其中11,000人 美国今年死于急性髓系白血病。AML的一种常见治疗方法是异基因干细胞移植 (AllSCT)。虽然有可能治愈，但接受异基因干细胞移植的患者中约有一半最终复发 然后死于他们的疾病。在异基因干细胞移植中，患者的免疫系统受到抑制，骨髓造血 将供者的造血干细胞和白细胞消融后再进行重组。捐赠者T细胞能够 识别来自受体遗传多态的多肽是外来的，并破坏呈现的细胞 他们。这些在供体和受体之间不同的多肽被称为次要组织相容性抗原。 (MHAS)。如果急性髓细胞白血病细胞上存在mHAs，供者T细胞将在所谓的移植物抗肿瘤中杀死急性髓细胞白血病细胞。 白血病(GVL)效应。然而，捐赠者T细胞也针对健康受体组织上出现的多肽，导致 一种威胁生命的副作用，称为移植物抗宿主病(GvHD)。将GVL与GvHD分开是一个关键 异基因干细胞移植生物学中的问题。仅在血液中表达的蛋白衍生的mHa的T细胞靶向 被认为是一种在不增加GvHD的情况下增加GVL的方法。我们假设两个人之间的关系不匹配。 供者和受者是AML异基因干细胞移植结局的关键决定因素。在这项工作中，我研究了MHA靶向 从MHA和T细胞两个角度对AML进行异基因SCT治疗。我的工作将阐明MHAS在异基因SCT中的作用， 丰富对AML预后的临床评估，并为未来的治疗靶向寻找新的MHAs。培训 在计算和湿实验室中，这里包含的免疫学将推进我的目标，成为一个独立的 受资助的内科医生和科学家，领导白血病免疫生物学研究实验室，照顾白血病患者。 我们使用3000多名异基因SCT患者的大数据集对MHAS进行了计算预测。在我们的MHA中- 聚焦目标1，我将使用质谱学来验证我们预测的mha，以确定它们是否存在。 在AML细胞系的细胞表面，因此可以作为T细胞的靶标。使用我验证的MHAS，我 将在统计学上定义预测由人类白细胞抗原呈现在细胞表面的多肽特征，从而为未来的MHA提供信息 身份鉴定工作。我还将评估验证的MHA与异基因SCT后临床结果之间的关系。 我将按人口频率分析美国境内所有种族的MHAS，目的是确定 覆盖所有种族的大多数急性髓系白血病患者的最小MHA集。 在我们专注于T细胞的目标2中，我们将评估患者是否耗尽了mhA特异性T细胞。 经历异基因干细胞移植后的复发。我们预测，这些T细胞的有效性可以预测异基因干细胞移植的成功 这些细胞的耗尽将伴随着复发。我们将调查衰竭标志物的表现和 异基因SCT患者复发前后MHA特异性T细胞释放促炎细胞因子的研究

Project Summary/Abstract Acute Myeloid Leukemia (AML) is a prevalent and deadly cancer, with a predicted 20,000 new cases and 11,000 deaths from AML this year in the US. A common treatment for AML is allogeneic stem cell transplantation (alloSCT). Though potentially curative, approximately half of all patients that receive alloSCT eventually relapse and die of their disease. In alloSCT, a patient’s immune system is suppressed and bone marrow hematopoiesis ablated then reconstituted with donor hematopoietic stem cells and leukocytes. Donor T cells are able to recognize peptides derived from recipient genetic polymorphisms as foreign and destroy the cells presenting them. These peptides that differ between donor and recipient are called minor histocompatibility antigens (mHAs). If mHAs are presented on AML cells, donor T cells will kill the AML cells in what is called the graft versus leukemia (GvL) effect. However, donor T cells also target peptides presented on healthy recipient tissues causing a life-threatening side effect called graft versus host disease (GvHD). Separating GvL from GvHD is a pivotal problem in alloSCT biology. T cell targeting of mHAs that are derived from proteins only expressed in the blood is viewed as a way to augment GvL without boosting GvHD. We hypothesize that mHAs mismatched between donor and recipient are a key determinant of alloSCT outcome for AML. In this work, I investigate mHA targeting in alloSCT for AML from two perspectives: mHA and T cell. My work will elucidate the role of mHAs in alloSCT, enrich clinical assessment of AML prognosis, and identify new mHAs for future therapeutic targeting. The training in computational and wet lab immunology included here will forward my goal of becoming an independently funded physician-scientist leading a research lab in leukemia immunobiology and caring for leukemia patients. We have computationally predicted mHAs using a large dataset of over 3000 alloSCT patients. In our mHA- focused Aim 1, I will validate our predicted mHAs using mass spectrometry to identify whether they are presented on the cell surface of AML cell lines and therefore can serve as targets for T cells. Using the mHAs I validate, I will statistically define peptide features that predict presentation on the cell surface by HLA, informing future mHA identification work. I will also assess associations between validated mHAs and clinical outcome after alloSCT. I will analyze mHAs by population frequency in all ethnic groups within the US, with the goal of identifying a minimal set of mHAs that cover the majority of AML patients of all ethnicities. In our T cell-focused Aim 2, we will assess whether T cells specific for mHAs are exhausted in patients experiencing relapse after alloSCT. We predict that efficacy of these T cells predict success of alloSCT, and that exhaustion of these cells will accompany relapse. We will investigate presentation of exhaustion markers and release of proinflammatory cytokines from mHA-specific T cells from alloSCT patients before and after relapse.