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

基本信息

批准号：
9982213
负责人：
John K. Wiencke
金额：
$ 79.74万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982213
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 Prognostic Factor Prognostic Marker Protocols documentation Resources Risk Risk Factors Role San Francisco Signal Transduction Stratification 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 outcome forecast patient population peripheral blood personalized cancer therapy prognostic value programs promoter public health relevance response success survival prediction tool tumor tumor DNA tumor microenvironment years of life lost

项目摘要

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癌症免疫的新型生物标志物的发展尚未跟上。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）的产生存在这种差距。我们的理解是癌症免疫治疗新时代公认的高度优先事项。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”。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在目标 1 中，我们将增强经过验证的表观遗传学测量神经胶质瘤患者的免疫抑制。白细胞谱的生物信息学方法包括粒细胞和单核细胞 MDSC。在目标 2 中，我们将使用特定的 DNA 甲基化变化作为免疫细胞类型的定量标记。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 成人神经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。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 Aim 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）为了探索血液和肿瘤免疫谱的关系，我们将应用它。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然后，我们将在 UCSF 患者群体中复制肿瘤血液相关性。综合计划将开发新工具来表征破坏性免疫抑制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。