Abstract
Retrospective observational studies have reported that statins improve clinical outcomes in patients previously treated with programmed cell death protein 1 (PD-1)-targeting monoclonal antibodies 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 β-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.
Highlights
Recent evidence has indicated that statins lead to better clinical outcomes in malignant pleural mesothelioma (MPM) and advanced nonsmall cell lung cancer (NSCLC) patients treated with the immune checkpoint inhibitor, nivolumab, a programmed cell death protein 1 (PD-1)-targeting monoclonal antibody, indicating that statins are available for combination cancer therapy with immune checkpoint inhibitors [18,19]
Previous observational reports have demonstrated that statins improve therapeutic efficacy and the overall survival in patients with advanced NSCLC who were previously treated with nivolumab, programmed cell death protein 1 (PD-1)-neutralizing monoclonal antibodies [18,19], the precise molecular mechanism by which statins are associated with anti-cancer effects of immune checkpoint inhibitors targeting the interaction of PD-1 and programmed death-ligand 1 (PD-L1), such as nivolumab and pembrolizumab, 3.1
Previous observational reports have demonstrated that statins improve therapeutic efficacy and the overall survival in patients with advanced NSCLC who were previously treated with nivolumab, programmed cell death protein 1 (PD-1)-neutralizing monoclonal antibodies [18,19], the precise molecular mechanism by which statins are associated with anti-cancer effects of immune checkpoint inhibitors targeting the interaction of PD-1 and programmed death-ligand 1 (PD-L1), such as nivolumab and pembrolizumab, been investigated
Summary
Oncogenic growth-signaling cascades, including phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT), mitogenactivated protein kinase (MAPK), CD44, c-Src, and c-Met, which are enriched in lipid rafts and related to both cancer development and progression, are tightly controlled by intracellular cholesterol levels [2,5]. Many preclinical and clinical studies have shown that abnormally increased cholesterol levels are associated with a higher cancer incidence and mortality, and cholesterol-lowering drugs, such as statins, exhibit beneficial effects in reducing the risk of cancer incidence and cancer-related mortality [2]. Several observational studies have demonstrated that statins have beneficial effects, including improving overall survival and reducing the risk of cancer-related mortality in patients with multiple types of cancers [7] such as prostate [8], colorectal [9], renal cell carcinoma [10], breast [11] and ovarian cancer [12], and lymphoma [13]. Statins suppress the enzymatic activation of Ras and Rho proteins, which play a central role in cancer development by inhibiting the prenylation of
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