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
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 un...
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PeerJ Inc.
2023-08-01
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| author | Bing Wang Tao Wang Chengzhe Yang Zhaodi Nan Dan Ai Xin Wang Huayang Wang Xun Qu Fengcai Wei |
| author_facet | Bing Wang Tao Wang Chengzhe Yang Zhaodi Nan Dan Ai Xin Wang Huayang Wang Xun Qu Fengcai Wei |
| author_sort | Bing Wang |
| collection | DOAJ |
| description | 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-κ B) inhibitor, PDTC, to determine whether A2BR regulates PD-L1 expression via the NF-κ 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-κ 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. |
| first_indexed | 2024-03-09T07:09:00Z |
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| language | English |
| last_indexed | 2024-03-09T07:09:00Z |
| publishDate | 2023-08-01 |
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| spelling | doaj.art-08c838642df64291afb0066a6d6b89c62023-12-03T09:10:01ZengPeerJ Inc.PeerJ2167-83592023-08-0111e1592210.7717/peerj.15922Co-inhibition of adenosine 2b receptor and programmed death-ligand 1 promotes the recruitment and cytotoxicity of natural killer cells in oral squamous cell carcinomaBing Wang0Tao Wang1Chengzhe Yang2Zhaodi Nan3Dan Ai4Xin Wang5Huayang Wang6Xun Qu7Fengcai Wei8Department of Oral and Maxillofacial Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University & Institute of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, ChinaDepartment of Oral and Maxillofacial Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University & Institute of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, ChinaDepartment of Oral and Maxillofacial Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University & Institute of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, ChinaInstitute of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, ChinaInstitute of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, ChinaDepartment of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, ChinaDepartment of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, ChinaInstitute of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, ChinaDepartment of Oral and Maxillofacial Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University & Institute of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, ChinaAdenosine 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-κ B) inhibitor, PDTC, to determine whether A2BR regulates PD-L1 expression via the NF-κ 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-κ 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.https://peerj.com/articles/15922.pdfOral squamous cell carcinomaCheckpoint inhibitorPD-L1A2BRNK cell |
| spellingShingle | Bing Wang Tao Wang Chengzhe Yang Zhaodi Nan Dan Ai Xin Wang Huayang Wang Xun Qu Fengcai Wei 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 PeerJ Oral squamous cell carcinoma Checkpoint inhibitor PD-L1 A2BR NK cell |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Oral squamous cell carcinoma Checkpoint inhibitor PD-L1 A2BR NK cell |
| url | https://peerj.com/articles/15922.pdf |
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