Phosphofructokinase 1 platelet isoform induces PD-L1 expression to promote glioblastoma immune evasion.
AKT
EGFR
PD-L1
PFKP
Tumor immune evasion
β-catenin
Journal
Genes & genomics
ISSN: 2092-9293
Titre abrégé: Genes Genomics
Pays: Korea (South)
ID NLM: 101481027
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
received:
01
04
2022
accepted:
18
07
2022
pubmed:
3
8
2022
medline:
26
11
2022
entrez:
2
8
2022
Statut:
ppublish
Résumé
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. We aimed to investigate the non-metabolic role of PFKP in PD-L1 expression-induced GBM immune evasion. 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. 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. These findings provide new mechanistic insight into the regulation of PD-L1 expression by a non-metabolic function of PFKP on tumor cells.
Sections du résumé
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.
Identifiants
pubmed: 35917090
doi: 10.1007/s13258-022-01291-4
pii: 10.1007/s13258-022-01291-4
doi:
Substances chimiques
B7-H1 Antigen
0
ErbB Receptors
EC 2.7.10.1
Protein Isoforms
0
PFKP protein, human
EC 2.7.1.11
Phosphofructokinase-1, Type C
EC 2.7.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1509-1517Informations de copyright
© 2022. The Author(s) under exclusive licence to The Genetics Society of Korea.
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