Functional analysis of the immune landscape in IDH mutant gliomas

IDH 突变神经胶质瘤免疫景观的功能分析

• 批准号: 10196469
• 负责人: VIVIANE TABAR
• 金额: $ 48.68万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196469
• 关键词: Acute Myelocytic Leukemia; Address; Affect; Antigen Presentation; Antigens; Autologous; Binding; Biological Assay; Biology; CD4 Positive T Lymphocytes; Cells; ChIP-seq; Cholangiocarcinoma; Clinical Trials; Conditioned Culture Media; CpG Islands; Data; Derivation procedure; Disease Progression; Down-Regulation; Enhancers; Environment; Enzymes; Epigenetic Process; Exposure to; Failure; Genes; Genetic Transcription; Genome; Genomics; Glioma; Goals; Grant; Hypermethylation; Immune; Immunity; Immunotherapeutic agent; Immunotherapy; Impairment; Infiltration; Inflammatory; Innate Immune Response; Isocitrate Dehydrogenase; Isocitrates; Knowledge; Leukocytes; Link; MHC Class II Genes; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Methods; Microglia; Molecular; Mutation; Natural Killer Cells; Oncogenes; Oncogenic; Pathogenicity; Pathologic; Patients; Peripheral; Phagocytosis; Phase; Phenotype; Primary Neoplasm; Prognosis; Public Health; Regulon; Research Personnel; Role; Sampling; Shapes; Source; Specific qualifier value; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Tumor-infiltrating immune cells; Work; combinatorial; cytokine; gain of function; immune function; inhibitor/antagonist; innovation; interest; macrophage; migration; monocyte; mutant; mutational status; novel; prognostic; response; transcription factor; tumor; tumor microenvironment; tumor-immune system interactions; tumorigenesis

PROJECT SUMMARY/ABSTRACT Malignant gliomas are primary brain cancers which can be prognostically stratified on the basis of a single mutation in the gene for isocitrate dehydrogenase (IDH). While gliomas are highly lethal cancers, the IDH mutation confers a significantly better prognosis, compared to IDH wild type gliomas, for unclear reasons. The IDH mutation results in a neomorphic gain of function which produces high levels of the oncometabolite R-2- hydroxyglutarate (2HG) and global genomic hypermethylation. IDH mutant gliomas are characterized by an immune quiescent tumor microenvironment, with significant infiltration with glioma associated macrophages and microglia (GAMs), and high levels of 2HG detected in the microenvironment. The central hypothesis is that 2HG promotes immune quiescence in IDH mutant glioma by specifying GAM function through activation of glioma-associated lineage determining transcription factors, leading to downregulation of antigen presentation capacity of GAMs, and inhibition of peripheral monocyte differentiation. The overarching goal of this study is to investigate how 2HG affects the immune function of GAMs, and how this in turn gives rise to an immune quiescent phenotype. The objective of this proposal is to determine the molecular basis for GAM specification and to develop immune functional assays and novel cellular platforms to interrogate the relationship between 2HG and GAM function in IDH mutant gliomas. The interest of the proposed work lies in providing greater understanding of the biology of the glioma tumor microenvironment in order to inform emerging immunotherapies, most of which have failed in glioma. In addition, IDH inhibitors have entered the clinical trial phase in gliomas, and it is critical to understand whether inhibiting 2HG could have an unintended consequences by reversing immune quiescence and leading to a pro-inflammatory tumor accelerating phenotype.

项目摘要/摘要 恶性神经胶质瘤是原发性脑癌 异位酸脱氢酶（IDH）的基因突变。而神经胶质瘤是高度致命的癌症，而IDH 与IDH野生型神经胶质瘤相比，突变的预后明显更好。这 IDH突变导致功能新形态增长，从而产生高水平的oncometabolite R-2- 羟基戊二酸（2HG）和全球基因组高甲基化。 IDH突变神经胶质瘤的特征是 免疫静脉肿瘤微环境，与胶质瘤相关巨噬细胞显着浸润 和小胶质细胞（GAM），以及在微环境中检测到的高水平的2HG。中心假设是 2HG通过激活指定GAM功能来促进IDH突变胶质瘤中的免疫静止 胶质瘤相关的谱系决定转录因子，导致抗原表现的下调 游戏的能力和抑制周围单核细胞分化。这项研究的总体目标是 研究2HG如何影响游戏的免疫功能，以及这又如何产生免疫力 静态表型。该建议的目的是确定GAM规范的分子基础 并开发免疫功能测定和新颖的细胞平台，以询问 IDH突变神经胶质瘤中的2HG和GAM功能。拟议工作的兴趣在于提供更大的 了解胶质瘤肿瘤微环境的生物学，以告知新兴 免疫疗法，其中大多数在神经胶质瘤中失败。此外，IDH抑制剂已进入临床试验 神经膜瘤的阶段，了解抑制2HG是否可能有意外 通过逆转免疫静止并导致促炎性肿瘤加速而产生的后果 表型。