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.
Institute of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
PeerJ. 2023 Aug 30;11:e15922. doi: 10.7717/peerj.15922. eCollection 2023.
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.
腺苷通过调节肿瘤微环境中的 T 细胞和自然杀伤 (NK) 细胞的功能来促进抗肿瘤免疫反应；然而，腺苷受体在口腔鳞状细胞癌 (OSCC) 进展中的作用及其对免疫检查点治疗的影响尚不清楚。在这项研究中，我们从 2014 年 2 月至 2016 年 12 月在山东大学齐鲁医院就诊的 80 例 OSCC 患者中获得了肿瘤组织。此后，我们使用免疫组织化学染色检测了腺苷 2b 受体 (A2BR) 和程序性死亡配体 1 (PD-L1) 的表达，并分析了肿瘤组织不同区域（如肿瘤巢、边界和癌旁基质）中它们表达之间的相关性。为了确定 A2BR 在 PD-L1 表达中的作用，我们用 BAY60-6583（A2BR 激动剂）处理 CAL-27（一种 OSCC 细胞系），并使用 Western blot 和流式细胞术测定 PD-L1 的表达。此外，我们用核转录因子-κB (NF-κB) 抑制剂 PDTC 处理 CAL-27，以确定 A2BR 是否通过 NF-κB 信号通路调节 PD-L1 表达。此外，我们进行了 Transwell 测定来验证 A2BR 和 PD-L1 对 NK 细胞募集的影响。我们的研究结果表明，A2BR 和 PD-L1 在 OSCC 中共同表达。此外，BAY60-6583 处理诱导 CAL-27 细胞中 PD-L1 的表达，而在用 PDTC 预处理的细胞中该表达部分降低，这表明 A2BR 激动剂通过诱导 NF-κB 信号通路诱导 PD-L1 表达。此外，OSCC 中高 A2BR 表达与 NK 细胞浸润减少有关。此外，我们的结果表明，用 MRS-1706（A2BR 反向激动剂）和/或 CD274（PD-L1 中和抗体）处理可促进 NK 细胞募集并增强对 OSCC 细胞的细胞毒性。总之，我们的研究结果强调了通过调节 NK 细胞募集和细胞毒性，协同抑制 A2BR 和 PD-L1 在 OSCC 治疗中的协同作用。
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