PD-1 阻断联合干扰素-α对肝细胞癌具有协同作用。
The combination of PD-1 blockade with interferon-α has a synergistic effect on hepatocellular carcinoma.
机构信息
Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
Institutes of Biomedical Sciences, Fudan University, 131 Dong An Road, Shanghai, 200032, China.
出版信息
Cell Mol Immunol. 2022 Jun;19(6):726-737. doi: 10.1038/s41423-022-00848-3. Epub 2022 Apr 22.
BACKGROUND
The efficacy of immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1) or its ligand 1 (PD-L1) antibody, in hepatocellular carcinoma (HCC) is limited, and it is recommended that they be combined with other therapies. We evaluated the combination of pegylated interferon-α (Peg-IFNα) with PD-1 blockade in HCC mouse models.
METHODS
We analyzed the effects of Peg-IFNα on tumor-infiltrating immune cells and PD-1 expression in the HCC immune microenvironment and examined the underlying mechanism of its unique effect on the PD-1 pathway. The in vivo efficacy of anti-PD-1 and Peg-IFNα was evaluated in both subcutaneous and orthotopic mouse models of HCC.
RESULTS
The combination of Peg-IFNα with PD-1 blockade dramatically enhanced T-cell infiltration, improved the efficacy of PD-1 antibody and prolonged mouse survival compared with PD-1 antibody monotherapy. Mechanistically, Peg-IFNα could recruit cytotoxic CD8 T cells to infiltrate the HCC microenvironment by inducing tumor cells to secrete the chemokine CCL4. Nevertheless, the HCC microenvironment quickly overcame the immune responses by upregulating PD-1 expression in CD8 T cells via the IFNα-IFNAR1-JAK1-STAT3 signaling pathway. The combination of PD-1 blockade with Peg-IFNα could restore the cytotoxic capacity of CD8 T cells and exerted a significant synergistic effect on HCC.
CONCLUSION
These results indicate that in addition to initiating the antitumor immune response itself, Peg-IFNα can also generate a microenvironment favoring PD-1 blockade. Thus, the combination of Peg-IFNα and PD-1 blockade can be a promising strategy for HCC.
背景
程序性细胞死亡蛋白-1（PD-1）或其配体 1（PD-L1）抗体等免疫检查点抑制剂（ICIs）在肝细胞癌（HCC）中的疗效有限，建议将其与其他疗法联合使用。我们评估了聚乙二醇化干扰素-α（Peg-IFNα）与 HCC 小鼠模型中 PD-1 阻断的联合作用。
方法
我们分析了 Peg-IFNα 对 HCC 免疫微环境中肿瘤浸润免疫细胞和 PD-1 表达的影响，并研究了其对 PD-1 通路的独特作用的潜在机制。在 HCC 的皮下和原位小鼠模型中评估了抗 PD-1 和 Peg-IFNα 的体内疗效。
结果
与 PD-1 抗体单药治疗相比，Peg-IFNα 与 PD-1 阻断联合使用可显著增强 T 细胞浸润，提高 PD-1 抗体的疗效并延长小鼠的存活时间。在机制上，Peg-IFNα 通过诱导肿瘤细胞分泌趋化因子 CCL4 来招募细胞毒性 CD8+T 细胞浸润 HCC 微环境。然而，HCC 微环境通过 IFNα-IFNAR1-JAK1-STAT3 信号通路上调 CD8+T 细胞中的 PD-1 表达，迅速克服了免疫反应。PD-1 阻断与 Peg-IFNα 的联合使用可以恢复 CD8+T 细胞的细胞毒性能力，并对 HCC 产生显著的协同作用。
结论
这些结果表明，Peg-IFNα 除了启动抗肿瘤免疫反应本身外，还可以产生有利于 PD-1 阻断的微环境。因此，Peg-IFNα 和 PD-1 阻断的联合使用可能是 HCC 的一种有前途的策略。
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