Phosphofructokinase 1 platelet isoform induces PD-L1 expression to promote glioblastoma immune evasion

Background Overexpression of PD-L1 is observed in many types of human cancer, including glioblastoma (GBM) and contributes to tumor immune evasion. In addition, GBM shows highly-activated aerobic glycolysis due to overexpression of phosphofructokinase 1 platelet isoform (PFKP), which the key enzyme in the glycolysis. However, it remains unclear whether the metabolic enzyme PFKP plays a role in the regulation of PD-L1 expression and GBM immune evasion. Objective We aimed to investigate the non-metabolic role of PFKP in PD-L1 expression-induced GBM immune evasion. Methods The mechanisms of PFKP-induced PD-L1 expression were studied by several experiments, including real-time PCR, immunoblot analysis, and ATP production. The coculture experiments using GBM cell and T cells were performed to evaluate the effect of PFKP on T cell activation. The clinical relationship between PFKP and PD-L1 was analyzed in The Cancer Genome Atlas (TCGA) database and in human GBM specimens. Results We showed that PFKP promotes EGFR activation-induced PD-L1 expression in human GBM cells. Importantly, we demonstrated that EGFR-phosphorylated PFKP Y64 plays an important role in AKT-mediated beta-catenin transactivation and subsequent PD-L1 transcriptional expression, thereby enhancing the GBM immune evasion. In addition, based on our findings, the levels of PFKP Y64 phosphorylation are positively correlated with PD-L1 expression in human GBM specimens, highlighting the clinical significance of PFKP Y64 phosphorylation in the GBM immune evasion. Conclusion These findings provide new mechanistic insight into the regulation of PD-L1 expression by a non-metabolic function of PFKP on tumor cells.

Automated summary

This study investigates the non-metabolic role of PFKP in GBM immune evasion. The results show that PFKP promotes PD-L1 expression through AKT-mediated signaling, thereby enhancing GBM immune evasion. Furthermore, the study finds a positive correlation between PFKP Y64 phosphorylation and PD-L1 expression in human GBM specimens, highlighting the clinical significance of PFKP Y64 phosphorylation in GBM immune evasion.