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.

项目摘要/摘要 神经胶质瘤是与免疫抑制有关的中枢神经肿瘤 影响肿瘤微环境，骨髓和外周血的网络 车厢。新型癌症免疫生物标志物的发展并没有使空间保持空间 我们对癌症相关感染的理解及其与之的关系的突破 造血异常和髓样相关抑制细胞（MDSC）的产生。这个差距 在癌症免疫疗法的新时代，我们的理解是公认的高优先事项。癌症 蓝色丝带面板推荐为关键目标“开发方法 克服儿童和成人的阻塞性，免疫抑制性肿瘤环境。” 项目通过开发和测试一种高度创新的方法来解决这一重要目标 测量神经胶质瘤患者的免疫抑制。在AIM 1中，我们将增加我们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球类型的定量标记。在目标2中，我们将 然后评估甲基化产生的免疫谱的预测值（CD4，CD8，T细胞，B- 细胞，NK，单核细胞，中性粒细胞，GMDSC，MMDSC）在患者的进展和存活中。 将从UCSF成人神经胶质瘤研究中仔细选择患者，以代表关键分子 胶质瘤的遗传亚型使用三个诊断基因突变（IDH，TERT，1P19Q缺失）。我们 然后将验证来自独立的神经胶质瘤患者的血液免疫特征 梅奥诊所。我们还将通过过采样罕见且不了解的理解来增强目标2 肿瘤患者的子集不包含三个基本突变中的任何一个（即三重 阴性神经胶质瘤）。为了探索血液和肿瘤免疫特征的关系，我们将应用 来自AIM 3的基因组广泛的甲基化测定 UCSF。然后，我们将复制梅奥诊所患者人群中的肿瘤血液相关性。这 综合计划将开发新工具来表征破坏性的免疫抑制 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子的主要进步。