Functional analysis of the immune landscape in IDH mutant gliomas

项目概要/摘要 恶性神经胶质瘤是原发性脑癌，其可以基于单个神经胶质瘤进行病理学分层。 异柠檬酸脱氢酶（IDH）基因突变。虽然神经胶质瘤是高度致命的癌症， 与IDH野生型神经胶质瘤相比，突变赋予显著更好的预后，原因尚不清楚。的 IDH突变导致功能的新变体增益，其产生高水平的癌代谢物R-2- 羟戊二酸（2 HG）和整体基因组超甲基化。IDH突变型神经胶质瘤的特征是 免疫静止肿瘤微环境，具有胶质瘤相关巨噬细胞的显著浸润 和小胶质细胞（GAM），以及在微环境中检测到的高水平的2 HG。核心假设是， 2 HG通过激活GAM功能促进IDH突变胶质瘤的免疫静止， 胶质瘤相关谱系决定转录因子，导致抗原呈递下调 GAM的能力，以及抑制外周单核细胞分化。本研究的总体目标是 研究2 HG如何影响GAM的免疫功能，以及这又如何引起免疫应答。 静止表型本提案的目的是确定GAM质量标准的分子基础 并开发免疫功能测定和新的细胞平台，以询问 2 HG和GAM在IDH突变型胶质瘤中的功能。拟议工作的利益在于提供更大的 了解神经胶质瘤肿瘤微环境的生物学，以告知新出现的 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 神经胶质瘤中的2 HG阶段，关键是要了解抑制2 HG是否会产生意想不到的 通过逆转免疫静止并导致促炎性肿瘤加速 表型

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.