Protein tyrosine phosphatase receptor type delta (PTPRD) suppresses the expression of PD-L1 in human hepatocellular carcinoma by down-regulating STAT3

Protein tyrosine phosphatase receptor type delta (PTPRD) is a tumor suppressor that is often inactivated in hepatocellular carcinoma (HCC). However, the mechanisms of how PTPRD inhibits HCC are not well understood. Programmed cell death ligand 1 (PD-L1), an immune checkpoint, plays a seminal role in the regulation of carcinogenesis of HCC. The sustained activation of STAT3 is closely related to PTPRD deletion and PD-L1 overexpression; however, whether there is a relationship between PTPRD and PD-L1 expression in HCC has not been investigated. This study aims to investigate the relationship between PTPRD and PD-L1 in HCC samples and illuminate potential new molecular mechanisms of PTPRD effects on PD-L1 in HepG2 cells.

The results from our study show that PTPRD and PD-L1 are negatively correlated in HCC tissues. PTPRD suppresses PD-L1 expression in HepG2 cells by down-regulating STAT3. These findings are expected to become a new target for the immunotherapy of HCC.

We collected 16 pairs of tumorous tissues and adjacent normal tissues from HCC patients. The mRNA and protein expression levels of PTPRD and PD-L1 in the HCC tissues were detected by RT-PCR and Western blot analysis. Next, Spearman's correlation analysis was performed to evaluate the relationship between PTPRD and PD-L1. Then, we transfected the overexpressed or knocked-down PTPRD genes into the HepG2 cell line, and the effects of PTPRD on PD-L1 in HCC cells were evaluated. The activity from the STAT3 and p-STAT3 in the HepG2 cells transfected with PTPRD gene overexpression and knockdown was determined by Western blotting tests.

The expression of PTPRD was significantly down-regulated in the HCC tissues compared with the adjacent control tissues; however, PD-L1 was significantly higher in the HCC tissues. There was a negative correlation between PTPRD and PD-L1 expression in the HCC tissues. PTPRD over-expression significantly inhibited PD-L1 expression; meanwhile, PTPRD depletion promoted PD-L1 expression in the HepG2 cells. Furthermore, PTPRD over-expression significantly inhibited the expression of STAT3 and p-STAT3, while PTPRD depletion promoted these cytokines. Our studies revealed that PTPRD repressed PD-L1 expression in the HepG2 cells, which might occur via the STAT3 pathway. Conclusions: The results from our study show that PTPRD and PD-L1 are negatively correlated in HCC tissues. PTPRD suppresses PD-L1 expression in HepG2 cells by down-regulating STAT3. These findings are expected to become a new target for the immunotherapy of HCC.