Regulation Of PD-L1 Induced By Glutamine Deprivation Occurs Through The Activation Of The EGFR/ERK/C-Jun Pathway In Renal Cancer

Objective:Glutamine is the basic substance to maintain tumor proliferation,which providing important nitrogen and carbon sources.Due to the characteristics of unlimited growth?proliferation and the aerobic glycolysis,compared with normal cells,tumors need more glutamine to maintain its proliferation.Therefore,tumors may be in a state of glutamine depletion because its requirement for glutamine may exceed its endogenous production.Programmed death-1(PD-1)and its ligand PD-L1 are important immunosuppressive molecules,which can make tumors escape from immunological surveillance,and this is the important mechanism of the occurrence and development of tumors.However,the regulative relationship between glutamine and PD-L1 was largely unknown.Our study explored the relationship between glutamine deprivation and PD-L1 expression in renal cell carcinoma and its specific signaling pathway.Methods:Real-time polymerase chain reaction,Western blot and Immunofluorescence were employed to explore the relationship between Glutamine and PD-L1.Then,we proved that glutamine can regulate the expression of PD-L1 through activating Epidermal growth factor receptor(EGFR).Next,we used EGFR-TKIs,EGF and ERK inhibitor to clarify the detailed signaling pathway involved in Glutamine regulation PD-L1.Finally,we examined the effect of tumor cells on T cells after induction of PD-L1 expression by ELISA kit.Results:We found that glutamine could regulate PD-L1 expression during glutamine is deprived.When glutamine is deprived,the expression of PD-L1 can be up-regulated by activating EGFR.By contrast,when the glutamine recovery,the up-regulated of PD-L1 can be restored to normal levels.When glutamine is deprived,activating EGFR by EGF could induce PD-L1 expression.Inhibiting EGFR by EGFR-TKIs and ERK inhibitor can reduce the up-regulation PD-L1 caused by the absence of glutamine.Therefore,glutamine up-regulates PD-L1 through EGFR/ERK/C-Jun pathway.Induction of the expression of PD-L1 in renal cancer cells after glutamine deprivation can inhibit the production of T cells IFN-?.Conclusion and significance:Our results first disclosed that glutamine regulate the expression of PD-L1 by EGFR/ERK/C-Jun pathway activation in renal cancer.In response to the glutaminedeficient tumor microenvironment,the renal cancer cells can acquire immune escape by up-regulation of PD-L1 and final realization of the progress of the tumor.Meanwhile,our results may provide a basis for the study of targeted metabolic drugs,EGFR-TKIs andanti-PD-1/PD-L1 antibodies combined treatment of renal cancer.However,this requires more studies to move into clinical practice.