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

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.

• Authors: 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
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 217 Issue 11 (11 02 2020) ISSN: 1540-9538 [Electronic] United States
• PMID: 32860047 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.

Chemical References

• Antibodies
• B7-H1 Antigen
• CD274 protein, human
• CTNNB1 protein, human
• Heterocyclic Compounds, 3-Ring
• MK 2206
• beta Catenin
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Allografts
• Animals
• Antibodies (immunology, pharmacology)
• B7-H1 Antigen (genetics, immunology, metabolism)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Glioblastoma (immunology, pathology)
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Humans
• Lymphocyte Activation (drug effects, genetics)
• Male
• Mice
• Mice, Inbred C57BL
• PTEN Phosphohydrolase (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Transcription, Genetic (genetics)
• Transfection
• Tumor Burden (drug effects, genetics)
• Tumor Escape (drug effects, genetics)
• beta Catenin (genetics, metabolism)