In cancer immunology, the programmed cell death 1/programmed cell death 1-ligand 1 (PD-1/PD-L1) pathway plays a major role, while anti-PD-1 and anti-PD-L1 antibodies are expected to provide reliable immunotherapy when give as treatment for various types of malignancy including lung cancer. PD-L1 expression in cancer cells has been reported to be a prognostic biomarker as well as a predictive factor for the therapeutic effects of immunotherapy. However, the mechanism of PD-L1 expression remains unclear. Since epithelial mesenchymal transition (EMT) is also known to have a key process in cancer progression, and also to be induced by several factors such as TGF-beta, FGF, and chemotherapy. We investigated the mechanism of PD-L1 expression as well as changes in its expression during the EMT process in non-small lung cancer (NSCLC). In addition, we examined the clinical significance of PD-L1 by analysis of clinical samples from patients with NSCLC.
To reveal the relationship of PD-L1 expression with the EMT process, A549 (human lung adenocarcinoma cell line) underwent EMT by treatment of TGF-beta or a chemotherapies treatment, then PD-L1 expression was evaluated using RT-PCR and western blotting assays. We also examined alterations of PD-L1 expression through a reverse-EMT process; mesenchymal-epithelial transition (MET) and EMT receptor kinase inhibitors. To elucidate the clinical significance of PD-L1 expression, we performed immunohistochemical staining analysis to evaluate the relationship of PD-L1 expression with EMT status in surgically resected specimens after chemotherapy from 23 patients with NSCLC.
Our results showed that PD-L1 gene expression was up-regulated through TGF-beta -induced EMT or the chemotherapy-induced EMT process, while that was down-regulated by EMT receptor-kinase inhibitor and through MET process. Furthermore, western blotting findings showed that PD-L1 protein changed through both EMT and MET as gene expression patterns. Analysis of clinical samples obtained from NSCLC cases revealed a significant relationship between PD-L1 expression and EMT status.
Our results suggested that PD-L1 expression is regulated by EMT status and those immunotherapies may circumvent the chemoresistance in NSCLC.
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Legal entity responsible for the study
KAKENHI Grants-in-Aid for Scientific Research) Grant-in-Aid for Scientific Research (C).
All authors have declared no conflicts of interest.