Interferon-γ induces immunosuppression in salivary adenoid cystic carcinoma by regulating programmed death ligand 1 secretion

Int J Oral Sci. 2022 Sep 28;14(1):47. doi: 10.1038/s41368-022-00197-x.

Abstract

Interferon-γ (IFN-γ), a key effector molecule in anti-tumor immune response, has been well documented to correlate with the intratumoral infiltration of immune cells. Of interest, however, a high level of IFN-γ has been reported in salivary adenoid cystic carcinoma (SACC), which is actually a type of immunologically cold cancer with few infiltrated immune cells. Investigating the functional significance of IFN-γ in SACC would help to explain such a paradoxical phenomenon. In the present study, we revealed that, compared to oral squamous cell carcinoma cells (a type of immunologically hot cancer), SACC cells were less sensitive to the growth-inhibition effect of IFN-γ. Moreover, the migration and invasion abilities of SACC cells were obviously enhanced upon IFN-γ treatment. In addition, our results revealed that exposure to IFN-γ significantly up-regulated the level of programmed death ligand 1 (PD-L1) on SACC cell-derived small extracellular vesicles (sEVs), which subsequently induced the apoptosis of CD8<sup>+</sup> T cells through antagonizing PD-1. Importantly, it was also found that SACC patients with higher levels of plasma IFN-γ also had higher levels of circulating sEVs that carried PD-L1 on their surface. Our study unveils a mechanism that IFN-γ induces immunosuppression in SACC via sEV PD-L1, which would account for the scarce immune cell infiltration and insensitivity to immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen / metabolism
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Carcinoma, Adenoid Cystic* / metabolism
  • Carcinoma, Adenoid Cystic* / pathology
  • Carcinoma, Squamous Cell* / pathology
  • Cell Line, Tumor
  • Humans
  • Immunosuppression Therapy
  • Interferon-gamma / metabolism
  • Interferon-gamma / pharmacology
  • Mouth Neoplasms* / metabolism
  • Programmed Cell Death 1 Receptor / metabolism
  • Salivary Gland Neoplasms* / pathology

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • IFNG protein, human
  • Programmed Cell Death 1 Receptor
  • Interferon-gamma