Methylseleninic acid overcomes programmed death-ligand 1-mediated resistance of prostate cancer and lung cancer.

Abstract

Programmed death-ligand 1 (PD-L1)-mediated resistance has become a great challenge for tumor treatment. Cisplatin increased tumor PD-L1 expression, promoted chemotherapy resistance. Interferon-γ (IFN-γ)-induced PD-L1 expression might facilitate immunotherapy resistance. Methylseleninic acid (MSeA), a selenium (Se) compound, offered superior cancer chemo-preventive activities and enhanced tumor sensitivity to diverse chemotherapeutic drugs. This study explored the effects of MSeA on the PD-L1-mediated resistance using both in vitro and in vivo models. Results showed that MSeA substantially attenuated cisplatin-induced PD-L1 expression via inhibiting protein kinase B phosphorylation, thereby potentiated cisplatin cytotoxicity in prostate and lung cancer cell models. In lung cancer xenograft model, MSeA significantly suppressed cisplatin-induced PD-L1 expression, consequently enhanced T-cell immunity, ultimately improved the therapeutic efficacy of cisplatin. Moreover, IFN-γ-induced tumor PD-L1 expression was remarkably reduced by MSeA, with correlated reductions in janus kinase 2 and signal transducer and activator of transcription 3 (STAT3) phosphorylation in prostate and lung cancer cell models. Our findings, for the first time, demonstrated that MSeA is a potential agent to overcome PD-L1-mediated chemotherapy and immunotherapy resistance. Such information might have potential clinical implications for prostate and lung cancer treatment.