PD-1 Carried on Small Extracellular Vesicles Leads to OSCC Metastasis

Immune checkpoint molecule PD-1, expressed on the cell surface, impairs antigen-driven activation of T cells and thus plays a critical role in tumorigenesis, progression, and the poor prognosis of oral squamous cell carcinoma (OSCC). In addition, increasing evidence indicates that PD-1 carried on sm...

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Bibliographic Details
Published in:Journal of dental research 2023-07, Vol.102 (7), p.795-805
Main Authors: Zhang, L.-Z., Yang, J.-G., Xia, H.-F., Huang, J., Liu, H.-M., Wu, M., Liu, B., Wang, W.-M., Chen, G.
Format: Article
Language:English
Subjects:
Animal models
Animals
Apoptosis
B7-H1 Antigen
Carcinoma, Squamous Cell - therapy
Cell activation
Cell cycle
Cell Line, Tumor
Cell migration
Cell Movement
Cell Proliferation
Cell surface
Epithelial-Mesenchymal Transition
Extracellular vesicles
Extracellular Vesicles - metabolism
Head and Neck Neoplasms
Humans
Immune checkpoint
Immunohistochemistry
Kinases
Lymph nodes
Lymphocytes T
MAP kinase
Mass spectroscopy
Metastases
Metastasis
Mice
Mouth Neoplasms - metabolism
Oral carcinoma
Oral squamous cell carcinoma
PD-1 protein
PD-L1 protein
Programmed Cell Death 1 Receptor
Senescence
Squamous Cell Carcinoma of Head and Neck
Therapeutic targets
Tumorigenesis
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Summary:Immune checkpoint molecule PD-1, expressed on the cell surface, impairs antigen-driven activation of T cells and thus plays a critical role in tumorigenesis, progression, and the poor prognosis of oral squamous cell carcinoma (OSCC). In addition, increasing evidence indicates that PD-1 carried on small extracellular vesicles (sEVs) also mediates tumor immunity, although their contributions to OSCC are yet unclear. Here, we investigated the biological functions of sEV PD-1 in patients with OSCC. The cell cycle, proliferation, apoptosis, migration, and invasion of CAL27 cell lines treated with or without sEV PD-1 were examined in vitro. We performed mass spectrometry to investigate the underlying biological process, combined with an immunohistochemical study of SCC7-bearing mice models and OSCC patient samples. In vitro data demonstrated that sEV PD-1 induced senescence and subsequent epithelial-mesenchymal transition (EMT) in CAL27 cells by ligating with tumor cell surface PD-L1 and activating the p38 mitogen-activated protein kinase (MAPK) pathway. Comprehensive immunohistochemical analysis of the xenograft mice models and OSCC patient samples revealed a very close correlation between the level of circulating sEV PD-1 and lymph node metastasis. These results demonstrate that circulating sEV PD-1 triggers senescence-initiated EMT in a PD-L1-p38 MAPK-dependent manner, contributing to tumor metastasis. It also suggests that the inhibition of sEV PD-1 may be a promising therapeutic target for the treatment of OSCC.
ISSN:0022-0345
1544-0591
DOI:10.1177/00220345231165209