PTEN loss in glioma cell lines leads to increased extracellular vesicles biogenesis and PD-L1 cargo in a PI3K-dependent manner.

IF 1.7 4区 教育学 Q2 EDUCATION & EDUCATIONAL RESEARCH
Julio C Sanchez, Timothy M Pierpont, Dariana Argueta-Zamora, Kristin Wilson, Avery August, Richard A Cerione
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引用次数: 0

Abstract

Phosphatase and Tensin Homologue (PTEN) is one of the most frequently lost tumor suppressors in cancer and the predominant negative regulator of the PI3K/AKT signaling axis. A growing body of evidence has highlighted the loss of PTEN with immuno-modulatory functions including the upregulation of the programmed death ligand-1 (PD-L1), an altered tumor derived secretome that drives an immunosuppressive tumor immune microenvironment (TIME), and resistance to certain immunotherapies. Given their roles in immunosuppression and tumor growth, we examined whether the loss of PTEN would impact the biogenesis, cargo, and function of extracellular vesicles (EVs) in the context of the anti-tumor associated cytokine interferon-γ (IFN-γ). Through genetic and pharmacological approaches, we show that PD-L1 expression is regulated by JAK/STAT signaling, not PI3K signaling. Instead, we observe that PTEN loss positively upregulates cell surface levels of PD-L1 and enhances the biogenesis of EVs enriched with PD-L1 in a PI3K-dependent manner. We demonstrate that because of these changes, EVs derived from glioma cells lacking PTEN have a greater ability to suppress T cell receptor (TCR) signaling. Taken together, these findings provide important new insights into how the loss of PTEN can contribute to an immunosuppressive TIME, facilitate immune evasion, and highlight a novel role for PI3K signaling in the regulation of EV biogenesis and the cargo they contain.

神经胶质瘤细胞系中 PTEN 的缺失会导致细胞外囊泡生物生成增加,并以 PI3K 依赖性方式增加 PD-L1 的载货量。
磷酸酶与天丝蛋白同源物(PTEN)是癌症中最常丢失的肿瘤抑制因子之一,也是 PI3K/AKT 信号轴的主要负调控因子。越来越多的证据表明,PTEN 的缺失具有免疫调节功能,包括程序性死亡配体-1(PD-L1)的上调和免疫抑制性肿瘤免疫微环境(TIME)的形成,而这很可能是分泌组改变的结果。鉴于它们在免疫抑制和肿瘤生长中的作用,这就提出了一个问题:PTEN 的缺失如何影响细胞外囊泡 (EV) 的生物发生和功能?在这里,我们发现胶质瘤细胞中这种肿瘤抑制因子的缺失伴随着产生富含 PD-L1 的 EVs 能力的增强,而这种能力在很大程度上依赖于 PI3K 的活性。我们进一步发现,从缺乏 PTEN 的胶质瘤细胞中提取的 EVs 对 IFN-γ 有更强的抑制 T 细胞受体(TCR)信号转导的能力。总之,这些发现为我们提供了重要的新见解,让我们了解 PTEN 的缺失如何导致免疫逃避,并突出了 PI3K 作为 EV 生物发生及其所含货物的新型调控因子的作用。
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来源期刊
CiteScore
6.20
自引率
12.90%
发文量
26
期刊介绍: Any educator in the environmental field will find The Journal of Environmental Education indispensable. Based on recent research in the sciences, social sciences, and humanities, the journal details how best to present environmental issues and how to evaluate programs already in place for primary through university level and adult students. University researchers, park and recreation administrators, and teachers from the United States and abroad provide new analyses of the instruction, theory, methods, and practices of environmental communication and education in peer-reviewed articles. Reviews of the most recent books, textbooks, videos, and other educational materials by experts in the field appear regularly.
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