RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
共抑制腺苷 2b 受体和程序性死亡配体 1 促进口腔鳞状细胞癌中 NK 细胞的募集和细胞毒性
英文原题：Co-inhibition of adenosine 2b receptor and programmed death-ligand 1 promotes the recruitment and cytotoxicity of natural killer cells in oral squamous cell carcinoma.
查看英文原题
Co-inhibition of adenosine 2b receptor and programmed death-ligand 1 promotes the recruitment and cytotoxicity of natural killer cells in oral squamous cell carcinoma.
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中文摘要
腺苷可通过调节肿瘤微环境中 T 细胞和自然杀伤（NK）细胞的功能促进抗肿瘤免疫反应，但腺苷受体在口腔鳞状细胞癌（OSCC）进展及其对免疫检查点治疗的影响尚不清楚。
本研究收集了 2014 年 2 月至 2016 年 12 月在山东大学齐鲁医院就诊的 80 例 OSCC 患者肿瘤组织。通过免疫组化检测腺苷 2B 受体（A2BR）和程序性死亡配体 1（PD-L1）的表达，并分析其在肿瘤组织不同区域（如肿瘤巢、边缘和癌旁基质）中的表达关联。为确定 A2BR 在 PD-L1 表达中的作用，研究使用 A2BR 激动剂 BAY60-6583 处理 OSCC 细胞系 CAL-27，并以 Western blot 和流式细胞术检测 PD-L1 表达。
此外，使用核转录因子 NF-κB 抑制剂 PDTC 处理 CAL-27，判断 A2BR 是否通过 NF-κB 信号通路调节 PD-L1。研究还开展 Transwell 实验，验证 A2BR 和 PD-L1 对 NK 细胞募集的影响。
结果显示，A2BR 和 PD-L1 在 OSCC 中共表达。BAY60-6583 处理诱导 CAL-27 细胞 PD-L1 表达；经 PDTC 预处理后，该效应部分减弱，提示 A2BR 激动剂通过诱导 NF-κB 信号通路促进 PD-L1 表达。
此外，OSCC 中 A2BR 高表达与 NK 细胞浸润较低相关。研究还显示，MRS-1706（A2BR 反向激动剂）和/或 CD274（PD-L1 中和抗体）治疗可促进 NK 细胞募集，并增强其对 OSCC 细胞的细胞毒性。
总之，本研究结果凸显联合抑制 A2BR 和 PD-L1 在 OSCC 治疗中的协同作用，其机制涉及调节 NK 细胞募集和细胞毒性。
展开英文摘要原文
Adenosine promotes anti-tumor immune responses by modulating the functions of T-cells and natural killer (NK) cells in the tumor microenvironment; however, the role of adenosine receptors in the progression of oral squamous cell carcinoma (OSCC) and its effects on immune checkpoint therapy remain unclear. In this study, we obtained the tumor tissues from 80 OSCC patients admitted at the Shandong University Qilu Hospital between February 2014 and December 2016.
Thereafter, we detected the expression of adenosine 2b receptor (A2BR) and programmed death-ligand 1 (PD-L1) using immunohistochemical staining and analyzed the association between their expression in different regions of the tumor tissues, such as tumor nest, border, and paracancer stroma. To determine the role of A2BR in PD-L1 expression, CAL-27 (an OSCC cell line) was treated with BAY60-6583 (an A2BR agonist), and PD-L1 expression was determined using western blot and flow cytometry.
Furthermore, CAL-27 was treated with a nuclear transcription factor-kappa B (NF- B) inhibitor, PDTC, to determine whether A2BR regulates PD-L1 expression via the NF- B signaling pathway.
Additionally, a transwell assay was performed to verify the effect of A2BR and PD-L1 on NK cell recruitment. The results of our study demonstrated that A2BR and PD-L1 are co-expressed in OSCC.
Moreover, treatment with BAY60-6583 induced PD-L1 expression in the CAL-27 cells, which was partially reduced in cells pretreated with PDTC, suggesting that A2BR agonists induce PD-L1 expression via the induction of the NF- B signaling pathway.
Furthermore, high A2BR expression in OSCC was associated with lower infiltration of NK cells.
Additionally, our results demonstrated that treatment with MRS-1706 (an A2BR inverse agonist) and/or CD274 (a PD-L1-neutralizing antibody) promoted NK cell recruitment and cytotoxicity against OSCC cells. Altogether, our findings highlight the synergistic effect of co-inhibition of A2BR and PD-L1 in the treatment of OSCC via the modulation of NK cell recruitment and cytotoxicity.
论文信息
- 作者
- Wang B、Wang T、Yang C、Nan Z、Ai D、Wang X、Wang H、Qu X
- 单位
- Department of Oral and Maxillofacial Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University & Institute of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.China
- 文献类型
- 非美国政府资助研究
- 期刊
- PeerJ2023
- 原文标识
- PubMed 37663280 · DOI 10.7717/peerj.15922
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