What question did this study set out to answer?

The aim is to understand how β-catenin activates PD-L1 expression to facilitate immune evasion in glioblastoma.

August 27, 2020Open Access

β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion

LDLinyong DuThe University of Texas MD Anderson Cancer Center JLJong‐Ho LeeDong-A University HJHongfei JiangXiamen University

Key Points

The aim is to understand how β-catenin activates PD-L1 expression to facilitate immune evasion in glioblastoma.
Examined the effects of Wnt ligand and activated EGFR on β-catenin/TCF/LEF complex binding to the CD274 promoter.
Utilized β-catenin depletion, AKT inhibition, and PTEN expression to assess changes in PD-L1 levels and CD8+ T cell activity.
Investigated the correlation of AKT-mediated β-catenin phosphorylation with PD-L1 and CD8+ T cell infiltration in human specimens.
β-Catenin depletion and AKT inhibition reduced PD-L1 expression, increased CD8+ T cell activation, and decreased tumor growth.
Combined treatment of an AKT inhibitor and anti-PD-1 antibody significantly enhanced anti-tumor effects.
In human glioblastoma specimens, higher levels of nuclear β-catenin and S552 phosphorylation correlated with increased PD-L1 and decreased CD8+ T cell infiltration.

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.

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