Oligodendrocyte transcription factor 2 orchestrates glioblastoma immune evasion by suppressing CXCL10 and CD8+ T cell activation
Xinchun Zhang, Jinjiang Xue, Cunyan Zhao, Chenqiuyue Zeng, Jiacheng Zhong, Gangfeng Yu, Xi Yang, Yao Ling, Dazhen Li, Jiaxiao Yang, Yun Xiu, Hongda Li, Shiyuan Hong, Liangjun Qiao, Song Chen, Q. Richard Lu, Yaqi Deng, Zhaohua Tang, Fanghui Lu
Xinchun Zhang, Jinjiang Xue, Cunyan Zhao, Chenqiuyue Zeng, Jiacheng Zhong, Gangfeng Yu, Xi Yang, Yao Ling, Dazhen Li, Jiaxiao Yang, Yun Xiu, Hongda Li, Shiyuan Hong, Liangjun Qiao, Song Chen, Q. Richard Lu, Yaqi Deng, Zhaohua Tang, Fanghui Lu
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Research Article Cell biology Immunology Oncology

Oligodendrocyte transcription factor 2 orchestrates glioblastoma immune evasion by suppressing CXCL10 and CD8+ T cell activation

Abstract

Glioblastomas (GBMs) are highly lethal brain tumors with limited treatment options and resistance to immune checkpoint inhibitors due to their immunosuppressive tumor microenvironment. Here, we identify OLIG2 as a key regulator of immune evasion in GBM stem-like cells, which inhibits CD8+ T cell–dependent antitumor immunity while promoting protumor macrophage polarization. Mechanistically, OLIG2 recruited HDAC7 to repress CXCL10 transcription, inducing STAT3 activation in tumor-associated macrophages (TAMs) and decreasing CD8+ T cell infiltration and activation. Genetic deletion of OLIG2 significantly increased CXCL10 secretion, shifting TAMs toward an antitumor phenotype and enhancing CD8+ T cell activities. Furthermore, upregulated OLIG2 expression was correlated with resistance to immune checkpoint inhibitors in patients with GBMs. OLIG2 inhibition by either genetic deficiency or pharmacological targeting with CT-179 sensitized GBM tumors to anti–PD-L1 therapy, enhancing antitumor immune responses and prolonging survival. Our findings reveal OLIG2+ glioma stem-like cells as critical mediators of immune evasion and identify the OLIG2/HDAC7/CXCL10 axis as a potential therapeutic target to enhance immune checkpoint inhibitor efficacy and improve immunotherapy outcomes in aggressive GBMs.

Authors

Xinchun Zhang, Jinjiang Xue, Cunyan Zhao, Chenqiuyue Zeng, Jiacheng Zhong, Gangfeng Yu, Xi Yang, Yao Ling, Dazhen Li, Jiaxiao Yang, Yun Xiu, Hongda Li, Shiyuan Hong, Liangjun Qiao, Song Chen, Q. Richard Lu, Yaqi Deng, Zhaohua Tang, Fanghui Lu

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Figure 3

CXCL10 promotes antitumor immune response of CD8+ T cells.

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CXCL10 promotes antitumor immune response of CD8+ T cells. (A) Heatmap s...
(A) Heatmap showing the expression of secreted proteins in the RNA-seq data of Ctrl-T and Olig2cKO GBM cells. (B) Venn diagram showing the shared secreted proteins among tumor tissue, spheres, and monolayers from Ctrl-T and Olig2cKO mice. (C) qPCR of mRNA expression of secreted proteins from Ctrl-T and Olig2cKO tumor cells (n = 3). (D) ELISA of CXCL10 secretion levels from the supernatant of Ctrl-T and Olig2cKO tumor cells (n = 3). (E) Correlation between OLIG2 and CXCL10 expression in TCGA GBM datasets and the Chinese Glioma Genome Atlas database. (F and G) qPCR of mRNA expression of CXCL10 in primary mouse GBM cells and U251 cells upon OLIG2 overexpression (OE) at 48 hours (n = 3). (H) Representative imaging and quantification of CXCL10 in GBM specimen with high or low OLIG2 expression (n = 19). Scale bars: 50 µm. (I) ELISA of CXCL10 secretion levels from the supernatant of Cxcl10-overexpressing GL261 cells (n = 3). (J) Quantification of migrated CD8+ T cells toward CM from the indicated treatment by transwell assay (n = 3). (K) Representative histograms and quantifications of CFSE proliferation assay of CD8+ T cells treated with CM from GL261-Ctrl and GL261-Cxcl10 OE cells for 72 hours (n = 3). (L) Representative plots and quantification of the IFN-γ expression of CD8+ T cells cocultured with GL261-Ctrl and GL261-Cxcl10 OE cells at the indicated ratio for 24 hours (n = 3). (M) Kaplan-Meier survival curves of orthotopic transplanted mice with Ctrl or Cxcl10 OE GL261 cells (n = 10 mice/group). Log-rank analysis was used to assess significance. (N and O) Flow cytometry quantification of the indicated T cells and macrophages in GBMs from orthotopic transplanted mice with GL261-Ctrl and GL261-Cxcl10 OE cells (n = 5/group). Statistical significance was determined by unpaired 2-tailed Student’s t test in C, D, F, G, I, K, L, N, and O; 2-way ANOVA in H; and 1-way ANOVA in J. *P < 0.05, **P < 0.01, ***P < 0.001.