KRAS mutations promote PD-L1-mediated immune escape by ETV4 in lung adenocarcinoma

Abstract

KRAS mutations are frequently associated with immune escape in lung adenocarcinoma. The aim of this research is to investigate the molecular mechanism underlying the KRAS-driven upregulation of PD-L1 and its role in immune escape. Methods: Transcriptomic data combined with data from the GEO database and immunohistochemistry were used to analyze the expression of PD-L1 in KRAS-mutant tissues. Functional experiments were performed using KRAS knockdown and MEK-ERK signaling pathway inhibitors to reveal the major signaling pathways by which KRAS mutations regulate PD-L1 expression. The key transcription factors regulating PD-L1 expression were identified through weighted gene coexpression network analysis (WGCNA) combined with dataset screening, and the binding sites of the key transcription factors to the PD-L1 promoter region were predicted using the JASPAR database and verified by luciferase reporting experiments and ChIP experiments. Flow cytometry, LDH assays, graft tumor assays, multicolor immunofluorescence and immunohistochemistry were used to determine whether key transcription factors affected PD-L1-mediated immune escape in KRAS-mutated lung adenocarcinoma. Results: PD-L1 expression was markedly increased in KRAS-mutant lung adenocarcinoma, and the MEK-ERK signaling pathway was identified as the main pathway promoting the upregulation of PD-L1. KRAS mutations promoted PD-L1 expression through the key transcription factor ETV4, which binds to specific sequences in the promoter region of PD-L1 to directly regulate its expression. KRAS mutations promoted PD-L1-mediated immune escape by ETV4. Conclusion: Carcinogenic KRAS mutations in lung adenocarcinoma regulate PD-L1 expression mainly through the MEK-ERK-ETV4 signaling axis. ETV4, as a transcription factor, activates PD-L1 expression and promotes immune escape in KRAS-mutant lung adenocarcinoma.