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

Interferon-gamma (IFN-gamma), 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-gamma 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-gamma 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-gamma. Moreover, the migration and invasion abilities of SACC cells were obviously enhanced upon IFN-gamma treatment. In addition, our results revealed that exposure to IFN-gamma 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(+) T cells through antagonizing PD-1. Importantly, it was also found that SACC patients with higher levels of plasma IFN-gamma also had higher levels of circulating sEVs that carried PD-L1 on their surface. Our study unveils a mechanism that IFN-gamma induces immunosuppression in SACC via sEV PD-L1, which would account for the scarce immune cell infiltration and insensitivity to immunotherapy.