The programmed death-ligand 1/programmed death-1 (PD-L1/ PD-1) pathway plays a pivotal role in the immune escape of tumors. Many tumor cells show "glutamine dependence." However, the relationship between glutamine metabolism and PD-L1 expression has not been reported. In this study, changes in PD-L1 expression in renal carcinoma cells were evaluated during glutamine deprivation and recovery. Although PD-L1 expression differed in two renal cancer cell lines, both cell lines upregulated PD-L1 during glutamine deprivation, and the upregulated PD-L1 was restored to normal after glutamine recovery. Mechanistically, glutamine deprivation resulted in activation of EGFR signaling via ERKs 1 and 2 (ERK1/2) and c-Jun. In addition, treatment of renal cancer cells with EGF also induced PD-L1 expression and ERK1/2 phosphorylation. Finally, inhibitors of EGFR, ERK, and c-Jun all inhibited phosphorylation of c-Jun and downregulated PD-L1 expression induced by glutamine deprivation. Taken together, the data suggest that glutamine regulates the expression of PD-L1 through the EGFR/ERK/c-Jun pathway in renal cancer.Implications: This study reveals glutamine deprivation induces PD-L1 expression via activation of EGFR/ERK/c-Jun signaling in renal cancer and provides novel markers for the treatment of renal cancer.

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