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

J Dent Res. 2023 Jul;102(7):795-805. doi: 10.1177/00220345231165209. Epub 2023 May 29.

Abstract

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.

Keywords: cancer biology; cell signaling; epithelial-mesenchymal transition; immunity; oral and maxillofacial surgery; oral carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen
  • Carcinoma, Squamous Cell* / therapy
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Epithelial-Mesenchymal Transition
  • Extracellular Vesicles* / metabolism
  • Head and Neck Neoplasms*
  • Humans
  • Mice
  • Mouth Neoplasms* / metabolism
  • Programmed Cell Death 1 Receptor
  • Squamous Cell Carcinoma of Head and Neck

Substances

  • B7-H1 Antigen
  • Programmed Cell Death 1 Receptor