Baicalein and baicalin promote antitumor immunity by suppressing PD-L1 expression in hepatocellular carcinoma cells
Baicalein and baicalin promote antitumor immunity by suppressing PD-L1 expression in hepatocellular carcinoma cells
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黄芩素和黄芩苷通过抑制肝癌细胞中PD-L1的表达来促进抗肿瘤免疫
DOI：
10.1016/j.intimp.2019.105824
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发表时间：
2019-10-01
影响因子：
5.6
通讯作者：
Dong, Jian
中科院分区：
文献类型：
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作者：
Ke, Mengyun;Zhang, Zhenhai;Dong, Jian
阻断PD-L1/PD-1通路以防止肿瘤细胞的免疫逃避是治疗多种癌症（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某些肿瘤具有直接的细胞毒性，在这里，我们证明除了直接的细胞毒性外，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应答。有趣的是，在黄芩素和黄芩苷治疗后，在BALB/c小鼠中观察到比在BALB/c-nu/nu小鼠中更显著的肿瘤消退。这两种黄酮类化合物在体外可显著抑制干扰素-γ（IFN-γ）诱导的PD-L1上调。黄芩素和黄芩苷都增强了T细胞清除肿瘤细胞的细胞毒性，这在用PD-L1过表达质粒转染HCC细胞或用抗PD-1阻断抗体预处理T细胞后被废除。进一步的机制研究表明，这两种黄酮类化合物均能抑制IFN-γ诱导的PD-L1表达和启动子活性，且这种作用是通过抑制STAT 3活性介导的。因此，黄芩素和黄芩苷降低STAT 3活性，进一步下调IFN-γ诱导的PD-L1表达，随后恢复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PD-L1表达下调抑制肿瘤生长，并表明这些黄酮类化合物具有巨大的临床治疗潜力。
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-gamma (IFN-gamma) 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 over-expression plasmid or after T cells were pretreated with an anti-PD-1 blocking antibody. Further mechanistic research indicated that the IFN-gamma-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-gamma-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.