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

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 PDL1 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.