Protein kinase D3 regulates the expression of the immunosuppressive protein, PD-L1, through STAT1/STAT3 signaling

Oral squamous cell carcinoma (OSCC) is capable of constructing a favorable immune escape environment through interactions of cells with cells and of cells with the environment. Programmed death ligand-1 (PD-L1) is a well-recognized inhibitor of anti-tumor immunity that plays an important role in tumor immune escape. However, the molecular mechanisms regulating PD-L1 expression are not yet fully understood. In this study, to investigate the role of protein kinase D3 (PKD3) in the regulation of PD-L1 expression, the expression and correlation of PKD3 and PD-L1 were first analyzed by the immunostaining of human OSCC tissue sections, cell experiments and TCGA gene expression databases. The expression levels of PKD3 and PD-L1 were found to be significantly higher in OSCC cells than in normal tissues or cells. In addition, the expression levels of PKD3 and PD-L1 were found to be significantly positively correlated. Subsequently, it was found that the levsel of PD-L1 expression decreased following the silencing of PKD3 and that the ability of interferon (IFN)-gamma to induce PD-L1 expression was also decreased in OSCC. The opposite phenomenon occurred following the overexpression of PKD3. It was also found that the phosphorylation of signal transducer and activator of transcription (STAT)1/STAT3 was reduced by the knockdown of PKD3 in OSCC. Moreover, the expression level of PD-L1 was decreased after the use of siRNA to knockdown STAT1 or STAT3. On the whole, the findings of this study confirm that PKD3 regulates the expression of PD-L1 induced by IFN-gamma by regulating the phosphorylation of STAT1/STAT3. These findings broaden the understanding of the biological function of PKD3, suggesting that PKD is a potential therapeutic target for OSCC.