Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan.
Department of Anatomic PathologyGraduate School of Medical SciencesKyushu UniversityFukuokaJapan.
Hepatol Commun. 2020 Dec 30;5(4):675-688. doi: 10.1002/hep4.1659. eCollection 2021 Apr.
The clinicopathological features of carcinomas expressing AT-rich interaction domain 1a (ARID1A) and programmed death ligand 1 (PD-L1) in HCC are poorly understood. Here, we examined ARID1A and PD-L1 expression in surgically resected primary hepatocellular carcinoma (HCC) and the association of ARID1A and PD-L1 expression with clinicopathological features and patient outcomes. Their association with ARID1A expression and tumor-associated CD68-positive macrophage was further explored. Using a database of 255 patients who underwent hepatic resection for HCC, immunohistochemical staining of ARID1A, PD-L1, and CD68 was performed. We also analyzed the expression PD-L1 after ARID1A knockdown in HCC cell lines. Samples from 81 patients (31.7%) were negative for ARID1A. Negative ARID1A expression was significantly associated with male sex, high alpha-fetoprotein, high des-gamma-carboxyprothrombin, large tumor size, high rate of poor differentiation, microscopic intrahepatic metastasis, and PD-L1 expression. In addition, negative ARID1A expression was an independent predictor for recurrence-free survival, overall survival, and positive PD-L1 expression. Stratification based on ARID1A and PD-L1 expression in cancer cells was also significantly associated with unfavorable outcomes. PD-L1 protein expression levels were increased through phosphoinositide 3-kinase/AKT signaling after ARID1A knockdown in HCC cells. HCC with ARID1A-low expression was significantly correlated with high levels of tumor-associated CD68-positive macrophage. Our large cohort study showed that ARID1A expression in cancer cells was associated with a poor clinical outcome in patients with HCC, PD-L1 expression in cancer cells, and tumor microenvironment. Therefore, ARID1A may be a potential molecular biomarker for the selection of patients with HCC for anti-programmed death 1/PD-L1 antibody therapy.
ARID1A 和 PD-L1 在 HCC 中的表达与临床病理特征和患者预后的关系尚不清楚。在这里，我们研究了手术切除的原发性肝细胞癌 (HCC) 中 ARID1A 和 PD-L1 的表达，并探讨了 ARID1A 和 PD-L1 表达与临床病理特征和患者预后的关系。还进一步探讨了它们与 ARID1A 表达和肿瘤相关 CD68 阳性巨噬细胞的关系。使用接受 HCC 肝切除术的 255 例患者的数据库进行了 ARID1A、PD-L1 和 CD68 的免疫组织化学染色。我们还分析了 HCC 细胞系中 ARID1A 敲低后 PD-L1 的表达。81 例患者（31.7%）的样本 ARID1A 呈阴性。阴性 ARID1A 表达与男性、高甲胎蛋白、高去γ-羧基凝血酶原、大肿瘤大小、高分化不良率、镜下肝内转移和 PD-L1 表达显著相关。此外，阴性 ARID1A 表达是无复发生存、总生存和阳性 PD-L1 表达的独立预测因子。基于癌细胞中 ARID1A 和 PD-L1 表达的分层也与不良结果显著相关。在 HCC 细胞中敲低 ARID1A 后，通过磷酸肌醇 3-激酶/AKT 信号通路增加 PD-L1 蛋白表达水平。ARID1A 低表达的 HCC 与肿瘤相关 CD68 阳性巨噬细胞水平显著相关。我们的大队列研究表明，癌细胞中的 ARID1A 表达与 HCC 患者的不良临床结局、癌细胞中的 PD-L1 表达和肿瘤微环境相关。因此，ARID1A 可能是 HCC 患者选择抗程序性死亡 1/PD-L1 抗体治疗的潜在分子生物标志物。
