Cao Xiaobo, Zhao Yang, Wang Jing, Dai Bingbing, Gentile Emanuela, Lin Jing, Pu Xingxiang, Ji Lin, Wu Shuhong, Meraz Ismail, Majidi Mourad, Roth Jack A
Department of Thoracic and Cardiovascular Surgery, Section of Thoracic Molecular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Oncotarget. 2017 Nov 21;8(64):107621-107629. doi: 10.18632/oncotarget.22581. eCollection 2017 Dec 8.
Expression of the tumor-suppressor gene in TUSC2-deficient NSCLC cells decreased PD-L1 expression and inhibited mTOR activity. Overexpressing TUSC2 or treatment with rapamycin resulted in similar inhibition of PD-L1 expression. Both TUSC2 and rapamycin decreased p70 and SK6 phosphorylation, suggesting that TUSC2 and rapamycin share the same mTOR target. Microarray mRNA expression analysis using TUSC2-inducible H1299 showed that genes that negatively regulate the mTOR pathway were significantly upregulated by TUSC2 compared with control. The presence of IFN-γ significantly increased PD-L1 expression in lung cancer cell lines, but overexpressing TUSC2 in these cell lines prevented PD-L1 from increasing in the presence of IFN-γ. Taken together, these findings show that TUSC2 can decrease PD-L1 expression in lung cancer cells. This ability to modify the tumor microenvironment suggests that TUSC2 could be added to checkpoint inhibitors to improve the treatment of lung cancer.
肿瘤抑制基因在TUSC2缺陷的非小细胞肺癌细胞中的表达降低了PD-L1的表达并抑制了mTOR活性。过表达TUSC2或用雷帕霉素处理导致对PD-L1表达的类似抑制。TUSC2和雷帕霉素均降低了p70和SK6的磷酸化，表明TUSC2和雷帕霉素共享相同的mTOR靶点。使用TUSC2诱导型H1299进行的微阵列mRNA表达分析表明，与对照相比，TUSC2显著上调了负调节mTOR途径的基因。IFN-γ的存在显著增加了肺癌细胞系中PD-L1的表达，但在这些细胞系中过表达TUSC2可防止PD-L1在IFN-γ存在时增加。综上所述，这些发现表明TUSC2可降低肺癌细胞中PD-L1的表达。这种改变肿瘤微环境的能力表明，TUSC2可添加到检查点抑制剂中以改善肺癌治疗。
