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

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Abstract

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 β-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.

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Data availability

All data generated during this study are included in this article.

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Acknowledgements

This work was supported by the Dong-A University research fund.

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Author notes

  1. Silu Wang, Su Hwan Park and Je Sun Lim contributed equally.

Authors and Affiliations

  1. Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China

    Silu Wang

  2. Department of Health Sciences, The Graduate School, Dong-A University, Busan, 49315, Republic of Korea

    Su Hwan Park, Je Sun Lim & Jong-Ho Lee

  3. Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea

    Yun-Yong Park

  4. Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Linyong Du

  5. Department of Biomedical Sciences, Dong-A University, Busan, 49315, Republic of Korea

    Jong-Ho Lee

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Contributions

SW, SHP, JSL, Y-YP, LD, and J-HL designed and performed experiments and analyzed data. SW, SHP, JSL, and J-HL wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Jong-Ho Lee.

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Wang, S., Park, S.H., Lim, J.S. et al. Phosphofructokinase 1 platelet isoform induces PD-L1 expression to promote glioblastoma immune evasion. Genes Genom 44, 1509–1517 (2022). https://doi.org/10.1007/s13258-022-01291-4

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