ATRX loss promotes immunosuppressive mechanisms in IDH1 mutant glioma

作者：Chengchen Hu, Kimberly Wang, Ceylan Damon, Yi Fu, Tengjiao Ma, Lisa E. Kratz, Bachchu Lal, Mingyao Ying, Shuli Xia, Daniel P. Cahill, Christopher M. Jackson, Michael Lim, John Laterra, Yun-Qing Li · 发表于：Neuro-Oncology · 年份：2021 · DOI：10.1093/neuonc/noab292 · 被引用次数：51 · 研究领域：Protein Degradation and Inhibitors、Glioma Diagnosis and Treatment、Chromatin Remodeling and Cancer

BACKGROUND: ATRX inactivation occurs with IDH1R132H and p53 mutations in over 80% of Grades II/III astrocytomas. It is believed that ATRX loss contributes to oncogenesis by dysregulating epigenetic and telomere mechanisms but effects on anti-glioma immunity have not been explored. This paper examines how ATRX loss contributes to the malignant and immunosuppressive phenotypes of IDH1R132H/p53mut glioma cells and xenografts. METHODS: Isogenic astrocytoma cells (+/-IDH1R132H/+/-ATRXloss) were established in p53mut astrocytoma cell lines using lentivirus encoding doxycycline-inducible IDH1R132H, ATRX shRNA, or Lenti-CRISPR/Cas9 ATRX. Effects of IDH1R132H+/-ATRXloss on cell migration, growth, DNA repair, and tumorigenicity were evaluated by clonal growth, transwell and scratch assays, MTT, immunofluorence and immunoblotting assays, and xenograft growth. Effects on the expression and function of modulators of the immune microenvironment were quantified by qRT-PCR, immunoblot, T-cell function, macrophage polarization, and flow cytometry assays. Pharmacologic inhibitors were used to examine epigenetic drivers of the immunosuppressive transcriptome of IDH1R132H/p53mut/ATRXloss cells. RESULTS: Adding ATRX loss to the IDH1R132H/p53mut background promoted astrocytoma cell aggressiveness, induced expression of BET proteins BRD3/4 and an immune-suppressive transcriptome consisting of up-regulated immune checkpoints (e.g., PD-L1, PD-L2) and altered cytokine/chemokine profiles (e.g., IL33, C...