IFN‐γ‐mediated inhibition of lung cancer correlates with PD‐L1 expression and is regulated by PI3K‐AKT signaling

Abstract

IFN-γ plays a crucial role in anti-tumor responses and also induces expression of PD-L1, a well-established inhibitor of anti-tumor immune function. Understanding how molecular signaling regulates the function of IFN-γ might improve its anti-tumor efficacy. Here, we show that the tumor expression of IFN-γ expression alone has no significant prognostic value in patients with locally advanced lung adenocarcinoma. Surprisingly, patients with tumors expressing both IFN-γ and PD-L1 have the best prognosis compared to those with tumors expressing IFN-γ or PD-L1 alone. Transcriptome analysis demonstrated that tumor tissues expressing IFN-γ 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-γ might serve as biomarker for the sensitivity of tumors to the inhibitory effect of IFN-γ. Mechanistic analysis revealed that in lung adenocarcinoma cells IFN-γ-induced activation of JAK2-STAT1 and PI3K-AKT pathways. The activation of JAK2-STAT1 is responsible for the anti-proliferative effect of IFN-γ. Inhibition of PI3K downregulated PD-L1 expression and enhanced the anti-proliferative effect of IFN-γ, suggesting that blockade of PI3K might maximize the IFN-γ-mediated anti-tumor effect. Our findings provide evidence for crosstalk between JAK2-STAT1 and PI3K-AKT pathways in response to IFN-γ in lung adenocarcinoma and have implications for the design of combinatorial targeted therapy and immunotherapy for the treatment of lung adenocarcinoma.

Plasma soluble programmed death ligand 1 levels predict clinical response in peripheral T‐cell lymphomas

“…Generally, soluble forms of receptors or ligands are usually produced through proteolytic cleavage of membrane‐bound proteins, such as sTNF and sB7‐H3, or by translation of alternative spliced mRNA, such as sCD86 . Report has suggested that IFN‐γ can induce upregulation of PD‐L1 expression . In this study, we indeed found that the levels of sPD‐L1 were positively correlated with IFN‐γ level in PTCL patients.…”

“…Programmed cell death protein 1 (PD‐1), as the receptor of PD‐L1, is usually expressed on the surface of immune cells, including activated T cells and monocytes . Studies have reported that PD‐L1 is mainly induced by inflammatory cytokines, such as interferon gamma (IFN‐γ) or other . Binding of PD‐L1 to PD‐1 can downregulate T‐cell responses, leading to immune suppression .…”

Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

“…Above finding prompted us to explore the potential mechanism(s) of PD‐L1 upregulation by CAFs. Prior literature suggests that PD‐L1 upregulated by some cytokines in tumor microenvironment, such as CCL15, IFN‐γ . To determined which cytokines expressed in CAFs were different from normal fibroblasts, qRT‐PCR was performed to scrutinize an amount of six CAFs cells.…”

“…In subsequent researches, we wanted to find the underlying mechanism by which CAFs influenced CXCL5 mediated the expression of PD‐L1. Previous researches have been reported that the oncogenic activation of RAS, AKT or TGF‐β signaling pathways control PD‐L1 expression in numerous cancers . We examined the total and phosphorylation levels of PI3K and AKT.…”

“…It is acknowledged that cytokines serve as mediators in shaping tumor microenvironment and facilitating tumor progression . Previous studies have reported that C‐X‐C motif chemokine ligand 12 (CXCL12), interferon‐γ (IFN‐γ), CXCL9/10/11 and IL6 promoted PD‐L1 expression in cancer cells . In this regard, we postulated that CAFs‐derived cytokines might promote PD‐L1 expression.…”