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.

中文翻译：

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甲基硒酸克服程序性死亡配体 1 介导的前列腺癌和肺癌耐药

程序性死亡配体 1 (PD-L1) 介导的耐药性已成为肿瘤治疗的一大挑战。顺铂增加肿瘤PD-L1表达，促进化疗耐药。干扰素-γ (IFN-γ) 诱导的 PD-L1 表达可能会促进免疫治疗抵抗。甲基硒酸 (MSeA) 是一种硒 (Se) 化合物，具有卓越的癌症化学预防活性，并增强了肿瘤对多种化学治疗药物的敏感性。本研究使用体外和体内模型探讨了 MSeA 对 PD-L1 介导的耐药性的影响。结果表明，MSeA 通过抑制蛋白激酶 B 磷酸化显着减弱顺铂诱导的 PD-L1 表达，从而增强顺铂在前列腺和肺癌细胞模型中的细胞毒性。在肺癌异种移植模型中，MSeA 显着抑制顺铂诱导的 PD-L1 表达，从而增强 T 细胞免疫，最终提高顺铂的治疗效果。此外，MSeA 显着降低了 IFN-γ 诱导的肿瘤 PD-L1 表达，与前列腺和肺癌细胞模型中 janus 激酶 2 和信号转导和转录激活因子 3 (STAT3) 磷酸化相关的降低。我们的研究结果首次证明，MSeA 是克服 PD-L1 介导的化疗和免疫治疗耐药性的潜在药物。这些信息可能对前列腺癌和肺癌治疗具有潜在的临床意义。与前列腺和肺癌细胞模型中 janus 激酶 2 和信号转导和转录激活因子 3 (STAT3) 磷酸化的相关减少。我们的研究结果首次证明，MSeA 是克服 PD-L1 介导的化疗和免疫治疗耐药性的潜在药物。这些信息可能对前列腺癌和肺癌治疗具有潜在的临床意义。与前列腺和肺癌细胞模型中 janus 激酶 2 和信号转导和转录激活因子 3 (STAT3) 磷酸化的相关减少。我们的研究结果首次证明，MSeA 是克服 PD-L1 介导的化疗和免疫治疗耐药性的潜在药物。这些信息可能对前列腺癌和肺癌治疗具有潜在的临床意义。