EBV-associated gastric cancer evades T-cell immunity by PD-1/PD-L1 interactions

BackgroundEpstein-Barr virus (EBV) is an oncogenic human herpesvirus involved in the development of around 10% of gastric cancers. The overexpression of PD-L1 is one of the features of EBV-associated gastric cancer (EBVaGC); however, the function of PD-L1 has not been studied in EBVaGC.MethodsWe used three EBVaGC cell lines, SNU719 cells, NCC24 cells, and YCCEL1 cells, to evaluate the PD-L1 expression and function in EBVaGC. Jurkat T-lymphocytes expressing PD-1 were co-cultured with NCC24 and YCCEL1 cells and the cell cycles were analyzed. To study the regulatory mechanism for PD-L1 expression, the 3UTR of PD-L1 was sequenced, and the effect of inhibitors of the IFN- signaling pathway was evaluated.ResultsAll of the EBVaGC cell lines expressed PD-L1, and its expression was further enhanced by stimulation with IFN-. In Jurkat T-cells co-cultured with IFN--stimulated NCC24 and YCCEL1 cells, the number of cells in the G0/G1 phase was significantly increased. This G0/G1 arrest was partially released by administration of anti-PD-L1 antibody. We found SNPs in PD-L1 3UTR nucleotide sequences that were located at seed regions for microRNAs. Treatment of EBVaGC cell lines with JAK2-inhibitor, PI3K-inhibitor, and mTOR inhibitor reduced the level of PD-L1 expression to the same level as cells without IFN- stimulation.ConclusionsEBVaGC cells expressing high levels of PD-L1 suppress T-cell proliferation, and the IFN- signaling pathway is involved in the expression of PD-L1.