Functional analysis of the immune landscape in IDH mutant gliomas

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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.