Interferon-gamma (IFN-gamma)-inducible protein 30 regulates the IFN-gamma pathway activation and PD-L1 levels in metastatic melanoma to determine immunotherapy responses 9092

Description Immunotherapy strategies are designed to target immune checkpoint inhibitors (ICIs) such as programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1). ICIs have successfully improved outcomes in metastatic melanoma (MM) patients. The PD-L1 levels in tumor cells are critical in controlling immune responses to ICIs; however, the regulatory mechanisms targeting PD-L1 in the context interferon-gamma (IFN-γ) pathways are not well understood. Here, we showed that the thiol reductase enzyme IFN-γ-inducible factor 30 (IFI30) determines the PD-L1 mRNA and protein levels by modulating the activation IFN-γ pathway. Briefly, IFI30 and PD-L1 levels are stimulated by IFN-γ in MM cell lines. IFI30 knockdown decreased the protein levels of interferon gamma receptor 1 (IFNGR1), which subsequently blocked IFN-γ pathway and decreased PD-L1 levels. We found that IFI30 neutralized cathepsin-L (CTSL) to reduce lysosomal protein degradation of IFNGR1 and PD-L1. Of clinical relevance, MM patients with high IFI30 levels showed: 1) better progression-free survival, 2) better responses to ICIs, and 3) increased infiltration levels of M1 macrophages, CD8+ and CD4+ T cells in MM from three independent datasets. In conclusion, IFI30 regulates the IFN-γ pathway activation and the PD-L1 levels during IFN-γ stimulation by neutralizing CTSL-mediated lysosomal protein degradation. IFI30 may represent a potential biomarker associated with better immune responses in MM patients receiving ICIs. Funding Sources This research program was supported by Dr. Miriam and Sheldon G. Adelson Medical Research Foundation to Dr. DSBH.