高血糖通过上调B7-H4在卵巢癌中促进肿瘤免疫逃避。

IF 3.5 3区 生物学 Q3 CELL BIOLOGY
Jing Yang, Jingjing Zhang, Zhenyan Wang, Lei Fu, Ming Liu, Zhaoyuan Niu
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引用次数: 0

摘要

背景:长期以来,ICB治疗对代谢性疾病(包括II型糖尿病)患者的疗效一直不太突出,但其潜在机制尚不清楚。目的:探讨高血糖在卵巢癌中对肿瘤免疫逃避和CD8+ T细胞功能的影响,重点探讨B7-H4和AP-1的作用。方法:采用2型糖尿病模型BKS db/db小鼠和ID8卵巢癌细胞,观察肿瘤生长、免疫细胞浸润以及高血糖对免疫检查点表达的影响。采用流式细胞术、Western blotting和染色质免疫沉淀(ChIP)方法探讨高血糖与B7-H4上调之间的分子机制。结果:与野生型对照相比,BKS db/db小鼠的肿瘤生长加速,对ICB治疗的反应性降低。由于CD8+ T细胞浸润减少,IFNγ产生减少,激活标记物(CD137和CD107a)减少,高血糖小鼠肿瘤中B7-H4的表达显著增加。体外高糖条件下,通过AP-1转录因子导致B7-H4在卵巢癌细胞中的表达增加。此外,AP-1的下调导致高血糖小鼠B7-H4表达降低,CD8+ T细胞浸润恢复,免疫激活增强。结论:本研究揭示高血糖通过ap -1介导的卵巢癌细胞B7-H4上调促进肿瘤免疫逃逸,导致CD8+ T细胞功能受损,ICB疗效降低。靶向AP-1/B7-H4轴可能为改善代谢紊乱患者的免疫治疗结果提供一种治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Hyperglycemia promotes tumor immune evasion via B7-H4 upregulation in ovarian cancer

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.
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来源期刊
Experimental cell research
Experimental cell research 医学-细胞生物学
CiteScore
7.20
自引率
0.00%
发文量
295
审稿时长
30 days
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.
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