Regorafenib enhances anti-tumor efficacy of immune checkpoint inhibitor by regulating IFN-γ/NSDHL/SREBP1/TGF-β1 axis in hepatocellular carcinoma.
Regorafenib enhances anti-tumor efficacy of immune checkpoint inhibitor by regulating IFN-γ/NSDHL/SREBP1/TGF-β1 axis in hepatocellular carcinoma.
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DOI：
10.1016/j.biopha.2023.114254
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发表时间：
2023-01
期刊：
影响因子：
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通讯作者：
Lulu Xie;Mingyu Liu;M. Cai;Wensou Huang;Yong-jian Guo;L. Liang;Weiguo Cai;Jianxin Liu;
中科院分区：
文献类型：
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作者：
Lulu Xie;Mingyu Liu;M. Cai;Wensou Huang;Yong-jian Guo;L. Liang;Weiguo Cai;Jianxin Liu;
免疫检查点抑制剂（ICI）在肝细胞癌（HCC）中的应答率较低，但ICI耐药的机制尚不清楚。干扰素-γ（IFN-γ）已被广泛确定为原型抗肿瘤细胞因子。然而，越来越多的研究表明IFN-γ也介导免疫抑制以促进肿瘤进展。在此，我们探讨了ICI诱导的IFN-γ是否可以激活免疫抑制性TGF-β1介导ICI抵抗。我们证明，胆固醇生物合成酶，NSDHL，在肝癌组织中减少，并与不良的临床预后。ICI诱导的IFN-γ降低NSDHL以激活SREBP 1，SREBP 1促进TGF-β1的产生，降低T细胞毒性并增强TGF 1浸润，导致ICI抵抗。我们还发现新型酪氨酸激酶抑制剂瑞戈非尼通过调节NSDHL/SREBP 1/TGF-β1轴显著逆转上述免疫抑制作用，从而增强瑞戈非尼联合ICI治疗HCC的效果。值得注意的是，瑞戈非尼联合ICI治疗在血清TGF-β1较高的HCC患者中更有效。IFN-γ诱导TGF-β1介导ICI抵抗。瑞戈非尼通过调节IFN-γ/NSDHL/SREBP 1/TGF-β1轴促进ICI抗肿瘤免疫应答。血清TGF-β1可作为预测瑞戈非尼联合ICI治疗HCC疗效的生物标志物。
Immune checkpoint inhibitor (ICI) shows low response rate in hepatocellular carcinoma (HCC) but the mechanisms underlying ICI resistance remains unclear. Interferon-γ (IFN-γ) has been widely determined as a prototypical antitumor cytokine. However, growing studies suggest that IFN-γ also mediates immunosuppression to promote tumor progression. Herein, we explored whether ICI-induced IFN-γ could activate immunosuppressive TGF-β1 to mediate ICI resistance. We demonstrated that cholesterol biosynthetic enzyme, NSDHL, was decreased in HCC tissues and associated with poor clinical prognosis. ICI-induced IFN-γ decreased NSDHL to activate SREBP1, which promoted TGF-β1 production, reduced T cell toxicity and enhanced Tregs infiltration, leading to ICI resistance. We also found that novel tyrosine kinase inhibitor, regorafenib, significantly reverse the above immunosuppressive effects by regulating NSDHL/SREBP1/TGF-β1 axis, which strengthened the effects of regorafenib plus ICI therapy against HCC. Noteworthily, regorafenib plus ICI therapy was more effective in HCC patients with higher serum TGF-β1. In conclusion, IFN-γ induced TGF-β1 to mediate ICI resistance. Regorafenib promotes anti-tumor immune response of ICI by regulating IFN-γ/NSDHL/SREBP1/TGF-β1 axis. Serum TGF-β1 may serve as a biomarker for predicting efficacy of regorafenib plus ICI therapy in HCC.