免疫检查点抑制剂（ICIs）是一种新兴的晚期肝细胞癌（HCC）治疗方法，然而，证据显示它们可能通过不明机制诱导高增进性疾病。本研究调查了ICIs对免疫细胞无物质条件下PD-L1携带的肝癌细胞的可能刺激作用。本研究中使用的11种人肝癌细胞系中，肉瘤HAK-5细胞系显示了最高的PD-L1表达。HLF细胞系表达中等水平，而HepG2、Hep3B和HuH-7细胞系则没有表达。此外，肉瘤型肝癌组织表达了高水平的PD-L1。我们观察到，在经过durvalumab和atezolizumab等抗PD-L1抗体处理48小时后，HAK-5细胞的细胞增殖约增加了20%，相比之下，对照IgG和抗PD-1抗体pembrolizumab处理的细胞没有增加。PD-L1非表达细胞对durvalumab或atezolizumab没有反应。在HAK-5和HepG2细胞中对PD-L1进行功能丧失和功能获得实验导致细胞增殖显著减少和增加。磷酸化受体酪氨酸激酶阵列和免疫沉淀实验显示肿瘤细胞中PD-L1与AXL之间存在直接相互作用，具有外部抗PD-L1抗体的稳定性与糖基化的PD-L1相关。AXL激活引发信号中继至Akt和Erk途径，促进体外和NOD/SCID小鼠异种移植瘤中的肿瘤细胞增殖。总之，这表明抗PD-L1抗体通过稳定PD-L1-AXL复合物，促进特定类型的肝癌细胞，包括具有间质成分的HCC的细胞增殖。治疗性抗PD-L1抗体通过稳定PD-L1-AXL复合物促进细胞增殖在PD-L1丰富的肿瘤中，包括具有间质成分的HCC。这种机制可能有助于高增进性疾病的发展。©2023. 亚太肝脏研究学会。

Immune checkpoint inhibitors (ICIs) are emerging treatments for advanced hepatocellular carcinoma (HCC); however, evidence has shown they may induce hyperprogressive disease via unexplained mechanisms.In this study, we investigated the possible stimulative effect of ICIs on programmed cell death-ligand 1 (PD-L1)-harboring liver cancer cells under immunocompetent cell-free conditions.The sarcomatous HAK-5 cell line displayed the highest expression of PD-L1 among 11 human liver cancer cell lines used in this study. HLF showed moderate expression, while HepG2, Hep3B, and HuH-7 did not show any. Moreover, sarcomatous HCC tissues expressed high levels of PD-L1. We observed approximately 20% increase in cell proliferation in HAK-5 cells treated with anti-PD-L1 antibodies, such as durvalumab and atezolizumab, for 48 h compared with that of those treated with the control IgG and the anti-PD-1 antibody pembrolizumab. No response to durvalumab or atezolizumab was shown in PD-L1-nonexpressing cells. Loss-of-function and gain-of-function experiments for PD-L1 in HAK-5 and HepG2 cells resulted in a significant decrease and increase in cell proliferation, respectively. Phosphorylated receptor tyrosine kinase array and immunoprecipitation revealed direct interactions between PD-L1 and AXL in tumor cells. This was stabilized by extrinsic anti-PD-L1 antibodies in a glycosylated PD-L1-dependent manner. Activation of AXL, triggering signal relay to the Akt and Erk pathways, boosted tumor cell proliferation both in vitro and in xenografted tumors in NOD/SCID mice.Collectively, this suggests that anti-PD-L1 antibodies stimulate cell proliferation via stabilization of the PD-L1-AXL complex in specific types of liver cancer, including in HCC with mesenchymal components.Therapeutic anti-PD-L1 antibodies promote cell proliferation by stabilizing the PD-L1-AXL complex in PD-L1-abundant neoplasms, including in HCC with mesenchymal components. Such a mechanism may contribute to the development of hyperprogressive disease.© 2023. Asian Pacific Association for the Study of the Liver.