Journal of Experimental Medicine, 27 August, 2020, DOI：https://doi.org/10.1084/jem.20191115

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.

Article link：https://rupress.org/jem/article/217/11/e20191115/152055/Catenin-induces-transcriptional-expression-of-PD