Tumor-intrinsic chromatin programs enforce immune evasion in glioblastoma
Raymond Sun, Chao Gao, Rongze Olivia Lu
Raymond Sun, Chao Gao, Rongze Olivia Lu
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Commentary

Tumor-intrinsic chromatin programs enforce immune evasion in glioblastoma

Abstract

Immunotherapy has shown limited efficacy in glioblastoma (GBM), reflecting profound immune evasion and an immunosuppressive microenvironment. In this Commentary, we highlight recent work by Zhang and colleagues identifying the transcription factor OLIG2 as a central mediator of immune evasion in GBM. Though OLIG2 has an established role in promoting GBM progression through its effects on glioma stem-like cells (GSCs), Zhang et al. demonstrated a further role for OLIG2 in suppressing antitumor immunity: in human GSCs and GSCs from mouse models of GBM, OLIG2 expression epigenetically repressed the interferon-responsive chemokine CXCL10, thereby limiting cytotoxic T cell infiltration. These findings provide a mechanistic explanation for immune resistance in GBM and support targeting tumor-intrinsic chromatin programs to enhance responses to immunotherapy.

Authors

Raymond Sun, Chao Gao, Rongze Olivia Lu

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Figure 1

OLIG2 promotes immune suppression in GBM.

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OLIG2 promotes immune suppression in GBM. (A) OLIG2 is an oligodendrocyt...
(A) OLIG2 is an oligodendrocyte transcription factor with known roles in tumor proliferation and phenotypic plasticity. Zhang et al. (4) have extended OLIG2’s contribution to GBM by demonstrating its role in limiting antitumor immunity. They reported that OLIG2 recruits HDAC7 to remove H3K27ac enhancers from CXCL10. The resulting decrease in CXCL10 signaling led to reductions in IFN signaling and CD8+ T cell infiltration as well as immunosuppressive polarization of tumor-associated macrophages, contributing to the “cold” immune phenotype that characterizes GBM. (B) In mouse models of GBM, the brain-penetrant OLIG2 inhibitor CT-179 enhanced CD8+ T cell activity and sensitized GBM tumors to PD-1/PD-L1 blockade in vivo, prolonging survival. OLIG2 targeting thus represents a potential strategy for reprogramming GBM to overcome immune resistance.