PMID- 37663280
OWN - NLM
STAT- MEDLINE
DCOM- 20230927
LR  - 20230927
IS  - 2167-8359 (Electronic)
IS  - 2167-8359 (Linking)
VI  - 11
DP  - 2023
TI  - 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.
PG  - e15922
LID - 10.7717/peerj.15922 [doi]
LID - e15922
AB  - 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-kappa B) inhibitor, PDTC, to determine whether A2BR 
      regulates PD-L1 expression via the NF-kappa 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-kappa 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.
CI  - (c)2023 Wang et al.
FAU - Wang, Bing
AU  - Wang B
AD  - 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.
FAU - Wang, Tao
AU  - Wang T
AD  - 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.
FAU - Yang, Chengzhe
AU  - Yang C
AD  - 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.
FAU - Nan, Zhaodi
AU  - Nan Z
AD  - Institute of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, 
      Shandong University, Jinan, China.
FAU - Ai, Dan
AU  - Ai D
AD  - Institute of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, 
      Shandong University, Jinan, China.
FAU - Wang, Xin
AU  - Wang X
AD  - Department of Pathology, School of Basic Medical Sciences, Cheeloo College of 
      Medicine, Shandong University, Jinan, China.
FAU - Wang, Huayang
AU  - Wang H
AD  - Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, 
      Shandong University, Jinan, China.
FAU - Qu, Xun
AU  - Qu X
AD  - Institute of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, 
      Shandong University, Jinan, China.
FAU - Wei, Fengcai
AU  - Wei F
AD  - 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.
LA  - eng
SI  - figshare/10.6084/m9.figshare.23266277.v1
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230830
PL  - United States
TA  - PeerJ
JT  - PeerJ
JID - 101603425
RN  - 0 (B7-H1 Antigen)
RN  - 0 (BAY 60-6583)
RN  - 0 (CD274 protein, human)
RN  - 0 (NF-kappa B)
RN  - 135467-92-4 (prolinedithiocarbamate)
RN  - 0 (Receptors, Adenosine A2)
RN  - 0 (Adenosine A2 Receptor Antagonists)
SB  - IM
MH  - Humans
MH  - B7-H1 Antigen/genetics
MH  - Drug Inverse Agonism
MH  - Killer Cells, Natural
MH  - *Mouth Neoplasms/drug therapy
MH  - NF-kappa B
MH  - *Squamous Cell Carcinoma of Head and Neck/drug therapy
MH  - Tumor Microenvironment
MH  - Receptors, Adenosine A2
MH  - *Adenosine A2 Receptor Antagonists/pharmacology
PMC - PMC10474825
OTO - NOTNLM
OT  - A2BR
OT  - Checkpoint inhibitor
OT  - NK cell
OT  - Oral squamous cell carcinoma
OT  - PD-L1
COIS- The authors declare that there are no competing interests.
EDAT- 2023/09/04 06:42
MHDA- 2023/09/05 06:42
PMCR- 2023/08/30
CRDT- 2023/09/04 04:58
PHST- 2023/06/01 00:00 [received]
PHST- 2023/07/28 00:00 [accepted]
PHST- 2023/09/05 06:42 [medline]
PHST- 2023/09/04 06:42 [pubmed]
PHST- 2023/09/04 04:58 [entrez]
PHST- 2023/08/30 00:00 [pmc-release]
AID - 15922 [pii]
AID - 10.7717/peerj.15922 [doi]
PST - epublish
SO  - PeerJ. 2023 Aug 30;11:e15922. doi: 10.7717/peerj.15922. eCollection 2023.