Interferon-alpha (IFN-α) is widely used in the clinical treatment of patients with chronic hepatitis B and hepatocellular carcinoma (HCC). However, high levels of CXCL8 are associated with resistance to IFN-α therapy and poorer prognosis in advanced cancers. In this study, we investigated whether IFN-α could directly induce the production of CXCL8 in HCC cells and whether CXCL8 could antagonize the antitumor activity of IFN-α. We found that IFN-α not only upregulated the expression of the inducible genes CXCL9, CXCL10, CXCL11 and PD-L1, but also significantly stimulated CXCL8 secretion in HCC cells. Mechanically, IFN-α induces CXCL8 expression by activating the AKT and JNK pathways. In addition, our results demonstrate that IFN-α exposure significantly increases the differentiation of HCC stem cells, but this effect is reversed by the addition of the CXCL8 receptor CXCR1/2 inhibitor Reparixin and STAT3 inhibitor Stattic. Besides, our study reveals that the cytokine CXCL8 secreted by IFN-α-induced HCC cells inhibits T-cell function. Conversely, inhibition of CXCL8 promotes TNF-α and IFN-γ secretion by T cells. Finally, liver cancer patients who received anti-PD-1/PD-L1 immunotherapy with high CXCL8 expression had a lower immunotherapy efficacy. Overall, our findings clarify that IFN-α triggers immunosuppression and cancer stem cell differentiation in hepatocellular carcinoma by upregulating CXCL8 secretion. This discovery provides a novel approach to enhance the effectiveness of HCC treatment in the future.

中文翻译：

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干扰素-α通过上调CXCL8分泌诱导肝癌干细胞分化和免疫抑制

干扰素-α（IFN-α）广泛用于临床治疗慢性乙型肝炎和肝细胞癌（HCC）患者。然而，高水平的 CXCL8 与晚期癌症对 IFN-α 治疗的耐药性和较差的预后相关。在本研究中，我们研究了IFN-α是否可以直接诱导HCC细胞中CXCL8的产生以及CXCL8是否可以拮抗IFN-α的抗肿瘤活性。我们发现IFN-α不仅上调诱导基因CXCL9、CXCL10、CXCL11和PD-L1的表达，而且还显着刺激HCC细胞中CXCL8的分泌。从机制上讲，IFN-α 通过激活 AKT 和 JNK 途径诱导 CXCL8 表达。此外，我们的结果表明，IFN-α暴露显着增加了HCC干细胞的分化，但通过添加CXCL8受体CXCR1/2抑制剂Reparixin和STAT3抑制剂Stattic可以逆转这种效果。此外，我们的研究表明，IFN-α诱导的肝癌细胞分泌的细胞因子CXCL8会抑制T细胞功能。相反，抑制 CXCL8 会促进 T 细胞分泌 TNF-α 和 IFN-γ。最后，接受CXCL8高表达的抗PD-1/PD-L1免疫治疗的肝癌患者的免疫治疗效果较低。总体而言，我们的研究结果阐明，IFN-α 通过上调 CXCL8 分泌来触发肝细胞癌中的免疫抑制和癌症干细胞分化。这一发现为未来增强 HCC 治疗的有效性提供了一种新方法。