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: 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
• 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

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.

项目总结/文摘