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ATRX loss promotes immunosuppressive mechanisms in IDH1 mutant glioma

Chengchen Hu1, Kimberly Wang1, Ceylan Damon1

  • 1Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland, USA.

Neuro-Oncology
|December 24, 2021
PubMed
Abstract

Insights

ATRX loss in astrocytoma promotes aggressive cell behavior and immune suppression by activating BET proteins. This immune-suppressive phenotype is enhanced by standard treatments but can be reversed by BET inhibitors.

Area of Science:

  • Molecular oncology
  • Cancer immunology
  • Epigenetics

Background:

  • ATRX inactivation is common in Grades II/III astrocytomas, often alongside IDH1R132H and p53 mutations.
  • While ATRX loss is linked to oncogenesis via epigenetic and telomere dysregulation, its impact on anti-glioma immunity remains unexplored.
  • This study investigates the role of ATRX loss in the malignant and immunosuppressive characteristics of IDH1R132H/p53mut glioma.

Purpose of the Study:

  • To elucidate how ATRX loss contributes to the aggressive and immunosuppressive phenotypes of IDH1R132H/p53mut glioma cells.
  • To explore the effects of ATRX loss on the immune microenvironment of astrocytoma.
  • To identify potential therapeutic targets for ATRX-deficient gliomas.

Main Methods:

  • Established isogenic astrocytoma cell lines with inducible IDH1R132H and/or ATRX loss using lentiviral and CRISPR/Cas9 systems.
  • Assessed cellular aggressiveness, DNA repair, and tumorigenicity through various in vitro and in vivo assays, including xenografts.
  • Quantified immune microenvironment modulators using qRT-PCR, immunoblotting, T-cell assays, macrophage polarization studies, and flow cytometry.

Main Results:

  • ATRX loss in IDH1R132H/p53mut astrocytoma cells increased aggressiveness and induced BET proteins (BRD3/4).
  • An immunosuppressive transcriptome with upregulated immune checkpoints (PD-L1, PD-L2) and altered cytokine profiles was observed.
  • ATRX loss promoted T-cell apoptosis, anti-inflammatory macrophage polarization, and Treg infiltration, with these effects exacerbated by temozolomide and radiation.

Conclusions:

  • ATRX loss activates a BRD-dependent immunosuppressive transcriptome in IDH1R132H/p53mut astrocytoma.
  • This leads to immune escape mechanisms within the tumor microenvironment.
  • Pharmacologic BET inhibition abrogated the immunosuppressive effects, suggesting a therapeutic strategy for ATRX-deficient gliomas.
Keywords:
ATRX lossBRD-dependent immune-suppressive transcriptomeIDH1 mutant astrocytomaglioma immune microenvironment

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