Mutant IDH modulates suppressive myeloid populations in malignant glioma.

in Clinical cancer research : an official journal of the American Association for Cancer Research by Eric P Grewal, Leland G K Richardson, Jing Sun, Rishab Ramapriyan, Maria Martinez-Lage, Julie J Miller, Bob S Carter, Daniel P Cahill, William T Curry, Bryan D Choi

TLDR

  • The study looked at how mutations in certain genes called IDH affect the way cells in the brain called gliomas work. The study found that mutations in IDH can change the way certain cells in the brain called myeloid cells work. The study used human brain samples and a mouse model to study this. The study found that mutations in IDH can cause a decrease in certain types of myeloid cells in the brain. The study also found that introducing the mutant IDH enzyme into a mouse model was enough to cause the same changes in the myeloid cells as seen in human brain samples. This study helps us understand how mutations in IDH can affect the way cells in the brain work and may help us find new ways to treat gliomas.

Abstract

Mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 have critical diagnostic and prognostic significance in diffuse gliomas. Neomorphic mutant IDH activity has been previously implicated in T-cell suppression; however, the effects of IDH mutations on intratumoral myeloid populations remain underexplored. Here, we investigate the influence of IDH status on the myeloid compartment using human glioma specimens and preclinical models. We performed RNA-sequencing and quantitative immunofluorescence on newly diagnosed, treatment-naive IDH-mutant grade 4 astrocytoma and IDH-wildtype glioblastoma (GBM) specimens. We also generated a syngeneic murine model, comparing transcriptomic and cell-level changes in paired isogenic glioma lines that differ only in IDH mutational status. Among patient samples, IDH-mutant tumors displayed underrepresentation of suppressive myeloid transcriptional signatures, which was confirmed at the cellular level with decreased numbers of intratumoral M2-like macrophages and MDSCs. Introduction of the IDH-mutant enzyme into murine glioma was sufficient to recapitulate the transcriptomic and cellular shifts observed in patient samples. We provide transcriptomic and cellular evidence that mutant IDH is associated with a quantitative reduction of suppressive myeloid cells in gliomas and that introduction of the mutant enzyme is sufficient to result in corresponding cellular changes using an in vivo preclinical model. These data advance our understanding of high-grade gliomas by identifying key myeloid cell populations that are reprogrammed by mutant-IDH and may be targetable through therapeutic approaches.

Overview

  • The study investigates the influence of isocitrate dehydrogenase (IDH) mutations on the myeloid compartment in diffuse gliomas using human glioma specimens and preclinical models. The study aims to understand the effects of IDH mutations on intratumoral myeloid populations and identify key myeloid cell populations that are reprogrammed by mutant-IDH and may be targetable through therapeutic approaches. The hypothesis being tested is that mutant IDH is associated with a quantitative reduction of suppressive myeloid cells in gliomas and that introduction of the mutant enzyme is sufficient to result in corresponding cellular changes using an in vivo preclinical model.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, specifically the influence of IDH mutations on the myeloid compartment in human glioma specimens and preclinical models. The results show that IDH-mutant tumors displayed underrepresentation of suppressive myeloid transcriptional signatures, which was confirmed at the cellular level with decreased numbers of intratumoral M2-like macrophages and MDSCs. Introduction of the IDH-mutant enzyme into murine glioma was sufficient to recapitulate the transcriptomic and cellular shifts observed in patient samples. The key findings of the study are that mutant IDH is associated with a quantitative reduction of suppressive myeloid cells in gliomas and that introduction of the mutant enzyme is sufficient to result in corresponding cellular changes using an in vivo preclinical model.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they identify key myeloid cell populations that are reprogrammed by mutant-IDH and may be targetable through therapeutic approaches. The study also highlights the importance of understanding the effects of IDH mutations on intratumoral myeloid populations in diffuse gliomas. Future research directions could include further exploration of the mechanisms underlying the reprogramming of myeloid cells by mutant-IDH, as well as the development of targeted therapies to modulate these cell populations in gliomas.
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