抑制ICAM1可通过β-catenin/PD-L1信号通路降低胶质母细胞瘤的干性并增强抗肿瘤免疫。

IF 15.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Meixia Guo,Zheng Yuan,Xiong Jin,Xinyu Li,Yilin Deng,Shuchang Zhou,Rui Niu,Joonbeom Bae,Jong Bae Park,Bingyang Shi,Jinlong Yin
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引用次数: 0

摘要

胶质母细胞瘤(GBM)干细胞(GSCs)在肿瘤发生、复发和治疗抵抗中起着关键作用,强调了它们在GBM复杂病理中的关键作用。尽管其重要性得到公认,但GSCs促进免疫逃避的机制,特别是在新兴的免疫疗法中,仍未完全了解。在这里,我们发现细胞间粘附分子1 (ICAM1)是GSC干性和致瘤性的关键调节因子,通过β-catenin/PD-L1信号传导促进免疫抑制微环境。机制上,ICAM1与ZNRF3相互作用,导致其自身泛素化和清除,稳定LRP6,激活β-catenin信号通路,上调PD-L1表达。在过表达icam1的GBM模型中,抗icam1和抗pd -1抗体联合治疗可获得最有效的肿瘤抑制,并显著延长生存期。细胞动力学和流式细胞术分析显示,ICAM1过表达通过PD-L1/PD-1相互作用减少细胞毒性CD8+ T细胞群,PD-1阻断可逆转。我们的研究结果强调了ICAM1和PD-1的共同靶向是对抗GBM免疫逃避的一种有希望的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of ICAM1 diminishes stemness and enhances antitumor immunity in glioblastoma via β-catenin/PD-L1 signaling.
Glioblastoma (GBM) stem cells (GSCs) are pivotal in tumor initiation, recurrence, and therapeutic resistance, underscoring their critical role in the complex pathology of GBM. Despite their recognized importance, the mechanisms by which GSCs facilitate immune evasion, especially in emerging immunotherapies, remain incompletely understood. Here, we identify intercellular adhesion molecule 1 (ICAM1) as a key regulator of GSC stemness and tumorigenicity, promoting an immunosuppressive microenvironment via β-catenin/PD-L1 signaling. Mechanistically, ICAM1 interacts with ZNRF3, leading to its autoubiquitination and clearance, stabilizing LRP6, and activating β-catenin signaling, which upregulates PD-L1 expression. Combined treatment with anti-ICAM1 and anti-PD-1 antibodies results in the most effective tumor inhibition and significantly extends survival in ICAM1-overexpressing GBM models. CyTOF and flow cytometry analyses reveal that ICAM1 overexpression reduces cytotoxic CD8+ T cell populations via PD-L1/PD-1 interactions, reversible by PD-1 blockade. Our findings highlight the co-targeting of ICAM1 and PD-1 as a promising strategy against immune evasion in GBM.
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来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
期刊介绍: Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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