Investigation On The Correlation Between KRAS Signalling And PD-L1 Expression

Programmed cell death 1(PD-1)is a critical immune checkpoint receptor in the immunoregulation,and its ligand,PD-L1,is up-regulated in many malignant tumors.PD-1 and PD-L1 deliver inhibitory signals that limit the activity of T cells,which plays a key role in autoimmune diseases,chronic infections,cancer and other diseases.Although the anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies,including melanoma,not all patients responded to treatments.The mechanism underlying PD-L1 expression in cancer is uncler.Objective:The aim of this study is to investigate the correlation between PD-L1 expression and KRAS signaling pathway,investigate the relevant molecular mechanisms,and evaluate the effects of KRAS signaling pathway on the prognostic value of PD-Ll.Methods:Firstly,Meta-analysis revealed the correlation between PD-L1 expression and KRAS mutation status of colorectal cancer patients.Secondly,in order to explore the impact of KRAS activity on the expression of PD-L1,the protein and mRNA expression of PD-LI were detected in KRAS mutant cell line and KRAS wildtype cell line using western blot,flow cytometry and real-time PCR.Then,the impact of KRAS activity on the PD-L1 expression induction by IFN-y was explored using western blot,real-time PCR and flow cytometry.Moreover,the role of MEK/ERK and mTOR pathways in PD-L1 expression were also explored using western blot,flow cytometry and real-time PCR.Finally,Meta-analysis evaluate the effects of KRAS mutation status of colorectal cancer patients on the prognostic value of PD-L1.Meta-analysis revealed that PD-L1 mRNA expression is elevated in KRAS mutant colorectal cancer patients.Our findings discovered significant increase of PD-L1 mRNA and protein expression in colon cancer cell lines with KRAS G12D mutation.Further studies on the effect of IFN-y on the expression of PD-L1 displayed that the KRAS mutation status affects PD-L1 expression in response to stimulation via MEK/ERK and mTOR pathway.Furthermore,a high level expression of PD-L1 was significantly correlated with a shorter survival time in patients with wild-type KRAS(P= 0.02)but not in those patients with mutant KRAS status.