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.
Zhang et al. (Tue,) studied this question.