TY - JOUR
T1 - β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion
AU - Du, Linyong
AU - Lee, Jong Ho
AU - Jiang, Hongfei
AU - Wang, Chengde
AU - Wang, Silu
AU - Zheng, Zhihong
AU - Shao, Fei
AU - Xu, Daqian
AU - Xia, Yan
AU - Li, Jing
AU - Zheng, Yanhua
AU - Qian, Xu
AU - Li, Xinjian
AU - Kim, Hyung Ryong
AU - Xing, Dongming
AU - Liu, Pengyuan
AU - Lu, Zhimin
AU - Lyu, Jianxin
N1 - Publisher Copyright:
© 2020 Rockefeller University Press. All rights reserved.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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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U2 - 10.1084/JEM.20191115
DO - 10.1084/JEM.20191115
M3 - Article
C2 - 32860047
AN - SCOPUS:85090177763
SN - 0022-1007
VL - 217
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 11
M1 - e20191115
ER -