Sokotrasterol Sulfate Suppresses IFN-γ-Induced PD-L1 Expression by Inhibiting JAK Activity

Area of Science:

• Immunology
• Marine Natural Products Chemistry
• Cancer Therapeutics

Background:

• Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway is a key regulator of immune responses in cancer.
• Monoclonal antibodies targeting PD-1/PD-L1 show therapeutic promise but developing non-antibody inhibitors remains a challenge.

Purpose of the Study:

• To develop a screening assay for identifying PD-L1 inhibitors from marine natural products.
• To investigate the potential of marine compounds as non-antibody immunotherapeutic agents targeting the PD-1/PD-L1 pathway.

Main Methods:

• Development of a flow cytometry assay to screen for PD-L1 inhibitory activity.
• Screening of 409 marine natural products.
• In vitro T cell-tumor cell coculture system to assess T-cell mediated killing.
• Mechanistic studies involving Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways.

Main Results:

• Sokotrasterol sulfate (SKS) was identified as a potent inhibitor of interferon-gamma (IFN-γ)-induced PD-L1 expression.
• SKS treatment sensitized tumor cells to antigen-specific T-cell mediated cytotoxicity.
• SKS was found to directly inhibit Janus kinase (JAK) activity, suppressing downstream Signal Transducer and Activator of Transcription (STAT) activation and PDL1 transcription.

Conclusions:

• Sokotrasterol sulfate (SKS) effectively suppresses PD-L1 expression through JAK/STAT pathway inhibition.
• SKS demonstrates immunotherapeutic potential by enhancing T-cell mediated tumor cell killing.
• SKS represents a promising non-antibody agent for cancer immunotherapy development.