β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion
Linyong Du, Jong‐Ho Lee, Hongfei Jiang, Chengde Wang, Silu Wang, Zhihong Zheng, Fei Shao, Daqian Xu, Yan Xia, Jing Li, Yanhua Zheng, Xu Qian, Xinjian Li, Hyung‐Ryong Kim, Dongming Xing, Pengyuan Liu, Zhimin Lu, Jianxin Lyu
Abstract
PD-L1 up-regulation in cancer contributes to immune evasion by tumor cells. Here, we show that Wnt ligand and activated EGFR induce the binding of the β-catenin/TCF/LEF complex to the CD274 gene promoter region to induce PD-L1 expression, in which AKT activation plays an important role. β-Catenin depletion, AKT inhibition, or PTEN expression reduces PD-L1 expression in tumor cells, enhances activation and tumor infiltration of CD8+ T cells, and reduces tumor growth, accompanied by prolonged mouse survival. Combined treatment with a clinically available AKT inhibitor and an anti-PD-1 antibody overcomes tumor immune evasion and greatly inhibits tumor growth. In addition, AKT-mediated β-catenin S552 phosphorylation and nuclear β-catenin are positively correlated with PD-L1 expression and inversely correlated with the tumor infiltration of CD8+ T cells in human glioblastoma specimens, highlighting the clinical significance of β-catenin activation in tumor immune evasion.