Statins Decrease Programmed Death-Ligand 1 (PD-L1) by Inhibiting AKT and β-Catenin Signaling

Retrospective observational studies have reported that statins improve clinical outcomes in patients previously treated with programmed cell death protein 1 (PD-1)-targeting monoclonal anti-bodies for malignant pleural mesothelioma (MPM) and advanced non-small cell lung cancer (NSCLC). In multiple mouse cancer models, de novo synthesis of mevalonate and cholesterol inhibitors was found to synergize with anti-PD-1 antibody therapy. In the present study, we investigated whether statins affect programmed death-ligand 1 (PD-L1) expression in cancer cells. Four statins, namely simvastatin, atorvastatin, lovastatin, and fluvastatin, decreased PD-L1 expression in melanoma and lung cancer cells. In addition, we found that AKT and beta-catenin signaling involved PD-L1 suppression by statins. Our cellular and molecular studies provide inspiring evidence for extending the clinical evaluation of statins for use in combination with immune checkpoint inhibitor-based cancer therapy.