Jing Yang, Jingjing Zhang, Zhenyan Wang, Lei Fu, Ming Liu, Zhaoyuan Niu
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引用次数: 0
Abstract
Background
The efficacy of ICB therapy has long been shown to be less prominent in patients with metabolic disorders, including type II diabetes, but the underlying mechanisms remain unclear.
Objective
To investigate how hyperglycemia influences tumor immune evasion and suppresses CD8+ T cell function in ovarian cancer, focusing on the role of B7-H4 and AP-1.
Methods
The BKS db/db mice, a model of type II diabetes, and ID8 ovarian cancer cells were used to evaluate tumor growth, immune cell infiltration, and the impact of hyperglycemia on immune checkpoint expression. Flow cytometry, Western blotting, and chromatin immunoprecipitation (ChIP) assays were performed to explore the molecular mechanisms linking hyperglycemia to B7-H4 upregulation.
Results
Accelerated tumor growth and reduced responsiveness to ICB therapy were observed in BKS db/db mice in comparison to wild-type controls. Tumors from hyperglycemic mice exhibited significantly higher expression of B7-H4 due to reduced CD8+ T cell infiltration, diminished IFNγ production, and decreased activation markers (CD137 and CD107a). In vitro, high-glucose conditions resulted in increased B7-H4 expression in ovarian cancer cells via the AP-1 transcription factor. Furthermore, the knockdown of AP-1 led to a reduction in B7-H4 expression, a restoration of CD8+ T cell infiltration, and an enhancement of immune activation in hyperglycemic mice.
Conclusion
This study reveals that hyperglycemia promotes tumor immune evasion through AP-1-mediated B7-H4 upregulation in ovarian cancer cells, resulting in impaired CD8+ T cell function and reduced ICB efficacy. Targeting the AP-1/B7-H4 axis could provide a therapeutic strategy to improve immunotherapy outcomes in patients with metabolic disorders.
期刊介绍:
Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.