IFN-?-mediated Inhibition Of Lung Cancer Correlates With PD-L1 Expression And Is Regulated By PI3K-AKT Signaling

IFN-? plays a crucial role in anti-tumor responses but also induces expression of PD-L1,a well-established inhibitor of anti-tumor immune function.Understanding how molecular signaling regulates the function of IFN-? might improve its anti-tumor efficacy.Here we show that the tumor expression of IFN-? expression alone has no significant prognostic value in patients with locally advanced lung adenocarcinoma.Surprisingly,patients with tumors expressing both IFN-? and PD-L1 have the best prognosis compared to those with tumors expressing IFN-? or PD-L1 alone.Transcriptome analysis demonstrated that tumor tissues expressing IFN-? display gene expression associated with suppressed cell cycle progression and expansion.Unexpectedly this profile was observed in PD-L1+ but not PD-L1-tumors.The current concept is that PD-L1 functions as a shield protecting tumor cells from cytolytic T cell(CTL)-mediated anti-tumor progression.However,our data indicate that PD-L1 expression in the presence of IFN-? might serve as biomarker for the sensitivity of tumors to the inhibitory effect of IFN-?.Mechanistic analysis revealed that in lung adenocarcinoma cells IFN-? induced activation of JAK2-STAT1 and PI3K-AKT pathways.The activation of JAK2-STAT1 is responsible for the anti-proliferative effect of IFN-?.Inhibition of PI3 K downregulated PD-L1 expression and enhanced the anti-proliferative effect of IFN-?(11)suggesting that blockade of PI3 K might maximize the IFN-?-mediated anti-tumor effect.Our findings provide evidence for crosstalk between JAK2-STAT1 and PI3K-AKT pathways in response to IFN-? in lung adenocarcinoma and have implications for the design of combinatorial targeted therapy and immunotherapy for the treatment of lung adenocarcinoma.