# Functional analysis of the immune landscape in IDH mutant gliomas

> **NIH NIH R21** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $486,750

## Abstract

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.

## Key facts

- **NIH application ID:** 10196469
- **Project number:** 1R21NS121812-01
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** VIVIANE TABAR
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $486,750
- **Award type:** 1
- **Project period:** 2021-04-15 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10196469

## Citation

> US National Institutes of Health, RePORTER application 10196469, Functional analysis of the immune landscape in IDH mutant gliomas (1R21NS121812-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10196469. Licensed CC0.

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