Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.
School of Dentistry, National Taiwan University, Taipei, Taiwan.
Cancer Sci. 2023 Oct;114(10):3857-3872. doi: 10.1111/cas.15919. Epub 2023 Jul 31.
The suppressive regulatory T cells (Treg) are frequently upregulated in cancer patients. This study aims to demonstrate the hypothesis that arecoline could induce the secretion of mitochondrial (mt) DNA D-loop and programmed cell death-ligand 1 (PD-L1) in extracellular vesicles (EVs), and attenuate T-cell immunity by upregulated Treg cell numbers. However, the immunosuppression could be reversed by whole glucan particle (WGP) β-glucan in oral squamous cell (OSCC) patients. Arecoline-induced reactive oxygen specimen (ROS) production and cytosolic mtDNA D-loop were analyzed in OSCC cell lines. mtDNA D-loop, PD-L1, IFN-γ, and Treg cells were also identified for the surgical specimens and sera of 60 OSCC patients. We demonstrated that higher mtDNA D-loop, PD-L1, and Treg cell numbers were significantly correlated with larger tumor size, nodal metastasis, advanced clinical stage, and areca quid chewing. Furthermore, multivariate analysis confirmed that higher mtDNA D-loop levels and Treg cell numbers were unfavorable independent factors for survival. Arecoline significantly induced cytosolic mtDNA D-loop leakage and PD-L1 expression, which were packaged by EVs to promote immunosuppressive Treg cell numbers. However, WGP β-glucan could elevate CD4 and CD8 T-cell numbers, mitigate Treg cell numbers, and promote oral cancer cell apoptosis. To sum up, arecoline induces EV production carrying mtDNA D-loop and PD-L1, and in turn elicits immune suppression. However, WGP β-glucan potentially enhances dual effects on T-cell immunity and cell apoptosis and we highly recommend its integration with targeted and immune therapies against OSCC.
抑制性调节 T 细胞（Treg）在癌症患者中经常上调。本研究旨在验证以下假设：槟榔碱可诱导线粒体（mt）DNA D 环和程序性细胞死亡配体 1（PD-L1）在细胞外囊泡（EV）中分泌，并通过上调 Treg 细胞数量来抑制 T 细胞免疫。然而，在口腔鳞状细胞癌（OSCC）患者中，全葡聚糖颗粒（WGP）β-葡聚糖可逆转免疫抑制。分析了 OSCC 细胞系中槟榔碱诱导的活性氧（ROS）产生和胞质 mtDNA D 环。还鉴定了 60 例 OSCC 患者的手术标本和血清中的 mtDNA D 环、PD-L1、IFN-γ和 Treg 细胞。我们证明，较高的 mtDNA D 环、PD-L1 和 Treg 细胞数量与较大的肿瘤大小、淋巴结转移、较晚的临床分期和咀嚼槟榔密切相关。此外，多变量分析证实，较高的 mtDNA D 环水平和 Treg 细胞数量是不利的独立生存因素。槟榔碱显著诱导胞质 mtDNA D 环渗漏和 PD-L1 表达，这些被 EV 包裹以促进免疫抑制性 Treg 细胞数量增加。然而，WGP β-葡聚糖可增加 CD4 和 CD8 T 细胞数量，减轻 Treg 细胞数量，并促进口腔癌细胞凋亡。总之，槟榔碱诱导携带 mtDNA D 环和 PD-L1 的 EV 产生，并由此引发免疫抑制。然而，WGP β-葡聚糖可能对 T 细胞免疫和细胞凋亡具有双重增强作用，我们强烈建议将其与针对 OSCC 的靶向和免疫治疗相结合。
