TUSC2 downregulates PD-L1 expression in non-small cell lung cancer (NSCLC).

Xiaobo Cao,Emanuela Gentile,Bingbing Dai,Jing Wang,Ismail Meraz,Yang Zhao,Shuhong Wu,Lin Ji,Jing Lin,Mourad Majidi,Jack A Roth,Xingxiang Pu

doi:10.18632/oncotarget.22581

Abstract

Expression of the TUSC2 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.

Highlights

Non-small cell lung carcinoma (NSCLC) is one of the most aggressive and devastating malignancies
TUSC2 reduction of PD-L1 expression in NSCLC cell lines is associated with reduced mTOR activity
We showed that overexpression of TUSC2, a unique tumor suppressor [18], has the potential to sensitize NSCLC to T cell–dependent www.impactjournals.com/oncotarget immunotherapy by altering the tumor microenvironment via PD-L1 downregulation

Summary

Introduction

Non-small cell lung carcinoma (NSCLC) is one of the most aggressive and devastating malignancies. Treatment of NSCLC with conventional cisplatin-based therapies has had limited success. Median overall survival with these therapies is about 10 months [1]. Various smallmolecule drugs have been used to target specific signaling pathways in lung cancer. Inhibitors that target the epidermal growth factor receptor pathway, have promising therapeutic value for the treatment of lung cancer [2]. Resistance to tyrosine kinase inhibitors is often acquired, leading to tumor progression

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