Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
J Exp Med. 2020 Nov 2;217(11). doi: 10.1084/jem.20191115.
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.
PD-L1 的上调导致肿瘤细胞的免疫逃逸。在这里，我们表明 Wnt 配体和激活的 EGFR 诱导 β-catenin/TCF/LEF 复合物与 CD274 基因启动子区域结合，从而诱导 PD-L1 的表达，其中 AKT 的激活起着重要作用。β-catenin 的耗竭、AKT 的抑制或 PTEN 的表达降低了肿瘤细胞中 PD-L1 的表达，增强了 CD8+T 细胞的激活和肿瘤浸润，并减少了肿瘤生长，同时延长了小鼠的存活时间。联合使用一种临床可用的 AKT 抑制剂和一种抗 PD-1 抗体可以克服肿瘤的免疫逃逸，并大大抑制肿瘤生长。此外，在人类脑胶质瘤标本中，AKT 介导的 β-catenin S552 磷酸化和核 β-catenin 与 PD-L1 的表达呈正相关，与 CD8+T 细胞的肿瘤浸润呈负相关，突出了 β-catenin 激活在肿瘤免疫逃逸中的临床意义。
