Immune epigenetic biomarkers of survival in glioma epidemiology

项目概要/摘要 神经胶质瘤是一种破坏性的中枢神经肿瘤， 影响肿瘤微环境、骨髓和外周血的网络 隔间癌症免疫的新生物标志物的发展没有跟上 我们对癌症相关炎症及其与癌症的关系的理解取得了突破， 异常造血和骨髓相关抑制细胞（MDSC）的产生。中的这一空白 我们的理解是癌症免疫治疗新时代公认的高度优先事项。癌症 Moonshot蓝丝带小组建议作为一个关键的可操作目标，“制定方法， 克服儿童和成人的阻碍性、免疫抑制性肿瘤环境”。我们 该项目通过开发和测试一种高度创新的方法来实现这一重要目标， 测量神经胶质瘤患者的免疫抑制。在目标1中，我们将增强我们验证的表观遗传 使用生物信息学方法来分析白细胞谱，包括粒细胞和单核细胞MDSC。我们 使用特异性DNA甲基化变化作为免疫细胞类型的定量标记。在目标2中， 然后评估甲基化产生的免疫谱（CD 4、CD 8、T细胞、B-T细胞）的预测值。 细胞、NK、单核细胞、嗜中性粒细胞、gMDSC、mMDSC）在胶质瘤患者进展和存活中的作用。 将从UCSF成人胶质瘤研究中仔细选择患者，以代表关键分子 使用三种诊断基因突变（IDH、TERT、1 p19 q缺失）的神经胶质瘤遗传亚型。我们 然后将在一个独立的神经胶质瘤患者群体中验证血液免疫谱， 马约诊所。我们还将通过对不常见且知之甚少的 其肿瘤不包含三个基本突变（即三重突变）中的任何一个的神经胶质瘤患者的子集 阴性胶质瘤）。为了探索血液和肿瘤免疫谱的关系，我们将应用 Aim 3中肿瘤的全基因组甲基化测定，来自患者的匹配血液样品来自 加州大学旧金山分校然后，我们将在马约诊所的患者人群中复制肿瘤血液相关性。这 一个综合性的项目将开发新的工具来描述破坏性免疫抑制的特征， 神经胶质瘤患者。我们的表观遗传免疫方法是高度灵活和成本效益，并将提供 这是评估免疫因素在胶质瘤治疗和预后中的重要进展。

Project Summary/Abstract Gliomas are devastating central nervous tumors that are associated with an immunosuppressive network impacting the tumor microenvironment, bone marrow and the peripheral blood compartments. The development of novel biomarkers of cancer immunity have not kept pace with breakthroughs in our understanding of cancer-associated inflammation and its relationship with abnormal hematopoiesis and the production of myeloid related suppressor cells (MDSC). This gap in our understanding is a recognized high priority in the new era of cancer immunotherapy. The Cancer Moonshot blue ribbon panel recommended as a key actionable goal “to develop approaches to overcome an obstructive, immune-suppressive tumor environment in both children and adults”. Our project addresses this important goal by developing and testing a highly innovative approach for measuring immunosuppression in glioma patients. In Aim 1 we will augment our validated epigenetic bioinformatic approach for leukocyte profiles to include both granulocytic and monocytic MDSCs. We use specific DNA methylation changes as quantitative markers of immune cell types. In Aim 2 we will then assess the predictive value of methylation generated immune profiles (CD4, CD8, T-cells, B- cells, NK, monocytes, neutrophils, gMDSC, mMDSC) in glioma patient progression and survival. Patients will be carefully selected from the UCSF Adult Glioma Study to represent key molecular genetic subtypes of glioma using three diagnostic gene mutations (IDH, TERT, 1p19q deletion). We then will validate the blood immune profiles in an independent population of glioma patients from the Mayo Clinic. We will also augment Aim 2 by oversampling an uncommon and poorly understood subset of glioma patients whose tumors do not contain any of the three cardinal mutations (i.e. triple negative glioma). To explore the relationship of blood and tumor immune profiles we will apply genome wide methylation assay to tumors in Aim 3 from patients with matched blood samples from UCSF. We will then replicate tumor blood correlations within the Mayo Clinic patient population. This comprehensive program will develop new tools to characterize the destructive immune suppression in glioma patients. Our epigenetic immune approach is highly flexible and cost effective and will provide a major advance for evaluating immune factors in glioma treatment and outcomes.