National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an 710061, Shaanxi Province, China; Institute of Advanced Surgical Technology and Engineering, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an 710061, Shaanxi Province, China.
Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China.
Int Immunopharmacol. 2019 Oct;75:105824. doi: 10.1016/j.intimp.2019.105824. Epub 2019 Aug 19.
Blocking the PD-L1/PD-1 pathway to prevent the immune evasion of tumor cells is a powerful approach for treating multiple cancers, including hepatocellular carcinoma (HCC). Previous studies have shown that baicalein and baicalin are directly cytotoxic to some tumors, here we demonstrate that in addition to direct cytotoxicity, these two flavonoids stimulate the T cell mediated immune response against tumors through reduction of PD-L1 expression in cancer cells. Interestingly, more significant tumor regression was observed in BALB/c mice than in BALB/c-nu/nu mice after baicalein and baicalin treatment. PD-L1 upregulation induced by interferon-γ (IFN-γ) was significantly inhibited by these two flavonoids in vitro. Both baicalein and baicalin enhanced the cytotoxicity of T cells to eliminate tumor cells, which was abrogated after HCC cells were transfected with a PD-L1 overexpression plasmid or after T cells were pretreated with an anti-PD-1 blocking antibody. Further mechanistic research indicated that the IFN-γ-induced expression and promoter activity of PD-L1 were suppressed by these two flavonoids, and these effects were mediated by STAT3 activity inhibition. Therefore, baicalein and baicalin decreased STAT3 activity, further downregulated IFN-γ-induced PD-L1 expression and subsequently restored T cell sensitivity to kill tumor cells. Our findings provide novel insight into the anticancer effects of baicalein and baicalin through which tumor growth is inhibited by PD-L1 expression downregulation and suggest that these flavonoids have great potential for clinical treatment.
阻断 PD-L1/PD-1 通路以防止肿瘤细胞免疫逃逸是治疗多种癌症（包括肝细胞癌[HCC]）的有效方法。先前的研究表明，黄芩素和黄芩苷对一些肿瘤具有直接细胞毒性，我们在此证明，除了直接细胞毒性外，这两种黄酮类化合物还通过降低癌细胞中 PD-L1 的表达来刺激 T 细胞介导的抗肿瘤免疫反应。有趣的是，在用黄芩素和黄芩苷处理后，BALB/c 小鼠比 BALB/c-nu/nu 小鼠观察到更显著的肿瘤消退。这两种黄酮类化合物在体外显著抑制干扰素-γ（IFN-γ）诱导的 PD-L1 上调。黄芩素和黄芩苷均增强 T 细胞的细胞毒性以消除肿瘤细胞，而在 HCC 细胞转染 PD-L1 过表达质粒或 T 细胞用抗 PD-1 阻断抗体预处理后，这种作用被消除。进一步的机制研究表明，这两种黄酮类化合物抑制 IFN-γ诱导的 PD-L1 的表达和启动子活性，并且这些作用是通过 STAT3 活性抑制介导的。因此，黄芩素和黄芩苷降低了 STAT3 活性，进一步下调了 IFN-γ诱导的 PD-L1 表达，随后恢复了 T 细胞杀伤肿瘤细胞的敏感性。我们的研究结果为黄芩素和黄芩苷的抗癌作用提供了新的见解，通过下调 PD-L1 表达抑制肿瘤生长，并表明这些黄酮类化合物在临床治疗方面具有巨大潜力。
