The mechanism of prostaglandin E2 upregulation of programmed death ligand 1 expression promoting immune escape in non-small cell lung cancer.

OBJECTIVE: Non-small cell lung cancer (NSCLC) represents a major contributor to cancer-related mortality. This study aims to investigate the prostaglandin E synthase (PTGES) role in NSCLC, especially how prostaglandin E2 (PGE2), which is synthesized by PTGES prompts programmed death ligand 1 (PD-L1) expression, resulting in immune escape. MATERIAL AND METHODS: The PTGES and PGE2 expression levels were tested in normal and NSCLC samples, respectively. An A549 cell line that overexpressed and knocked down PTGES was established, and cell multiplication, colony formation, and aggression were evaluated. The PD-L1 levels and cytotoxicity effect of CD8(+) T cells were analyzed by co-culture with A549 cells. The expression levels of proteins involved in phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and the effect of activation and inhibition on PD-L1 expression were investigated. The effect of PGE2 was further verified by establishing an in vivo xenograft mouse model. RESULTS: The expression of PTGES in NSCLC cells notably increased compared with that in control cells (P < 0.001). Correspondingly, a significant upregulation of PGE2 levels was observed (P < 0.001). Overexpression of PTGES enhanced cell proliferation and aggression ability (P < 0.001), whereas knockdown of PTGES weakened these capabilities (P < 0.01). In the experiment of co-culture with CD8(+) T cells, PD-L1 was upregulated (P < 0.01) and cytotoxicity was considerably reduced (P < 0.01) in the PTGES overexpression group. Meanwhile, PD-L1 was downregulated (P < 0.01) and cytotoxicity was enhanced (P < 0.01) in the PTGES knockdown group. Overexpression of PTGES was able to activate the PI3K/AKT/mTOR pathway (P < 0.01). Activation and inhibition of this pathway showed that PGE2 upregulated PD-L1 expression through this signaling pathway (P < 0.01). The mouse transplanted tumor model further verified the effect of PTGES expression on tumor growth and immune escape. CONCLUSION: This study confirmed that PGE2 promotes immune evasion of NSCLC by upregulating PD-L1, and the mechanism involves the activation of the PI3K/AKT/mTOR pathway. This research provides a novel theoretical basis for immunotherapy of NSCLC and emphasizes the clinical value of PTGES/PGE2 as a potential target.