Immune epigenetic biomarkers of survival in glioma epidemiology

项目摘要/摘要 胶质瘤是一种破坏性的中枢神经系统肿瘤，与免疫抑制有关。 影响肿瘤微环境、骨髓和外周血的网络 车厢。癌症免疫的新生物标志物的发展还没有跟上 我们对癌症相关炎症及其与癌症的关系的理解取得突破 异常造血和髓系相关抑制细胞(MDSC)的产生。这一差距在 在癌症免疫治疗的新时代，我们的理解是公认的高度优先事项。巨蟹座 建议将登月蓝丝带面板作为关键的可操作目标，以开发方法 在儿童和成人中克服阻碍、免疫抑制的肿瘤环境“。我们的 Project通过开发和测试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，我们将增强我们已验证的表观遗传学 包括粒细胞和单核细胞MDSCs的白细胞图谱的生物信息学方法。我们 使用特定的DNA甲基化变化作为免疫细胞类型的定量标记。在《目标2》中我们将 然后评估甲基化产生的免疫特征(CD4、CD8、T细胞、B细胞)的预测价值 细胞、NK、单核细胞、中性粒细胞、gMDSC、mMDSC)在脑胶质瘤患者进展和生存中的作用。 患者将从加州大学旧金山分校的成人脑胶质瘤研究中精心挑选，以代表关键分子 应用三种基因突变(IDH、TERT、1p19q缺失)诊断脑胶质瘤的遗传亚型。我们 然后将验证一组独立的胶质瘤患者的血液免疫图谱 梅奥诊所。我们还将通过对一个不常见且理解不足的样本进行过采样来增强目标2 胶质瘤患者的子集，其肿瘤不包含三种基本突变中的任何一种(即三重突变 阴性胶质瘤)。为了探索血液和肿瘤免疫图谱的关系，我们将应用 AIM 3患者的全基因组甲基化检测 加州大学旧金山分校。然后，我们将在梅奥诊所的患者群体中复制肿瘤血液相关性。这 综合计划将开发新的工具来表征破坏性免疫抑制 神经胶质瘤患者。我们的表观免疫方法具有高度的灵活性和成本效益，将提供 评价免疫因素在脑胶质瘤治疗和预后方面的重大进展。

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.