Newcastle Disease Virus - Induced Interferons Regulate PD-L1 and MICA Expression in Human Tumor and Normal Cells.

PURPOSE: To explore whether NDV and/or NDV-induced IFNs regulate programmed death-1 ligand (PD-L1) expression and modulate the balance between inhibitory and stimulatory immune signals. MATERIALS AND METHODS: Human non-malignant (NB1RGB and HEK293) and tumor (A549 and U87MG) cell lines were used. Cells were either infected with Newcastle disease virus (NDV) LaSota strain or treated with interferons (IFNs). PD-L1 expression was analyzed by flow cytometry, Western blotting, and immunofluorescence. The relationship between PD-L1, as an immune inhibitor, and major histocompatibility complex class I polypeptide-related sequence A (MICA), as an immune activator, was evaluated using duplex chromogenic in situ hybridization. To investigate whether the NDV-induced shift in the PD-L1/MICA axis was sufficient to activate natural killer group 2 member D (NKG2D) receptor-possessing cells within peripheral blood mononuclear cells (PBMCs), IFN-γ production was measured in PBMCs following 24 hours of co-culture with tumor and normal cell lines previously infected with NDV or treated with IFN-λ. RESULTS: NDV infection and IFN treatment resulted in a reduction of PD-L1 expressions in specific cell types. This decrease was accompanied by a concurrent increase in MICA expression, as demonstrated by in situ hybridization. The shift in balance between PD-L1 and MICA correlated with enhanced activation of NKG2D receptor-expressing immune cells, evidenced by increased IFN-γ secretion. CONCLUSION: These findings suggest that NDV may exert antitumor effects by modulating the balance between inhibitory checkpoint molecules and stimulatory ligands, specifically through downregulation of PD-L1 and upregulation of MICA. This mechanism highlights the potential of NDV to enhance cytotoxic immune responses and supports its further development as a novel strategy in cancer immunotherapy.