Immune epigenetic biomarkers of survival in glioma epidemiology

神经胶质瘤流行病学中生存的免疫表观遗传生物标志物

• 批准号: 10224109
• 负责人: John K. Wiencke
• 金额: $ 54.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224109
• 关键词: 19q; Accounting; Address; Adult; Adult Glioma; Age; American; Archives; B-Lymphocytes; Bioinformatics; Biological; Biological Assay; Blood; Blood Cells; Blood specimen; Bone Marrow; CD8-Positive T-Lymphocytes; Cells; Child; Classification; Classification Scheme; Clinic; Correlation Studies; DNA; DNA Methylation; Data; Development; Diagnosis; Diagnostic; Disease Progression; Elements; Environment; Epidemiology; Epigenetic Process; Exclusion; Fingerprint; Fluorescence-Activated Cell Sorting; Foundations; Future; Gene Mutation; Generations; Glioma; Gliomagenesis; Goals; Heart; Hematopoiesis; Immune; Immune System Diseases; Immune checkpoint inhibitor; Immunologic Factors; Immunologic Markers; Immunologics; Immunophenotyping; Immunosuppression; Immunotherapeutic agent; Inflammation; Inherited; Intervention; Leukocytes; Libraries; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Medicine; Methylation; Molecular; Molecular Genetics; Mutation; Myelogenous; Myeloid-derived suppressor cells; Myelopoiesis; Paraffin Embedding; Patient-Focused Outcomes; Patients; Peripheral; Population; Predictive Value; Production; Prognosis; Prognostic Factor; Prognostic Marker; Protocols documentation; Resources; Risk Factors; Role; San Francisco; Signal Transduction; Suppressor-Effector T-Lymphocytes; Techniques; Technology; Testing; The Cancer Genome Atlas; Therapeutic; Time; Treatment outcome; Tumor Immunity; Tumor Markers; Vaccines; Variant; base; cancer immunotherapy; cancer site; cancer therapy; cell type; clinical decision-making; cost effective; epigenetic marker; flexibility; genome wide methylation; granulocyte; immunological status; improved; in vitro Model; innovation; methylome; monocyte; neutrophil; novel marker; patient population; peripheral blood; personalized cancer therapy; prognostic value; programs; promoter; public health relevance; response; risk prediction; risk stratification; success; survival prediction; tool; tumor; tumor DNA; tumor microenvironment; years of life lost

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.

项目概要/摘要 神经胶质瘤是一种破坏性中枢神经肿瘤，与免疫抑制相关 影响肿瘤微环境、骨髓和外周血的网络 隔间。癌症免疫的新型生物标志物的发展并没有跟上 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 造血异常和骨髓相关抑制细胞（MDSC）的产生。这个差距在 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 登月蓝带小组被推荐为一个关键的可行目标“开发方法 克服儿童和成人的阻塞性、免疫抑制性肿瘤环境”。我们的 项目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，我们将增强经过验证的表观遗传学 白细胞谱的生物信息学方法包括粒细胞和单核细胞 MDSC。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谱（CD4、CD8、T 细胞、B- 细胞、NK、单核细胞、中性粒细胞、gMDSC、mMDSC）在神经胶质瘤患者进展和生存中的作用。 患者将从 UCSF 成人胶质瘤研究中精心挑选，以代表关键分子 使用三种诊断基因突变（IDH、TERT、1p19q 缺失）确定神经胶质瘤的遗传亚型。我们 然后将验证来自独立神经胶质瘤患者群体的血液免疫特征 梅奥诊所。我们还将通过对不常见且知之甚少的情况进行过采样来增强目标 2 胶质瘤患者的子集，其肿瘤不包含任何三种主要突变（即三重突变） 阴性神经胶质瘤）。为了探索血液和肿瘤免疫谱的关系，我们将应用 对 Aim 3 中的肿瘤进行全基因组甲基化分析，该分析来自具有匹配血液样本的患者 加州大学旧金山分校。然后，我们将在梅奥诊所患者群体中复制肿瘤血液相关性。这 综合计划将开发新工具来表征破坏性免疫抑制 神经胶质瘤患者。我们的表观遗传免疫方法高度灵活且具有成本效益，并将提供 评估神经胶质瘤治疗和结果中免疫因素的重大进展。