Background: The role of immune profiling and tumor budding in hepatocellular carcinoma (HCC) remains largely unknown. This study evaluated the association between tumor budding and lymphocytic infiltration in HCC. Meanwhile, HCC patients were stratified based on tumor budding grade and immune score. Patients and methods: A total of 423 HCC patients were divided into training (n = 212) and validation (n = 211) cohort. Tumor slides from resected HCC samples were used for tumor budding assessment. A prognosis-relevant immune score was developed based on five types of immune cells out of eleven immune markers. A classification based on tumor budding grade and immune type was established (IS-TB type). To explore the association of IS-TB type and molecular alterations of HCC, 100 HCC samples and adjacent non-tumor tissues from 100 patients were investigated by whole-exome sequencing. Results: Tumor budding was an independent adverse prognostic factor for OS and DFS in both of the training and validation cohorts (all P values <.05). The rate of high-grade tumor budding was significantly higher in HCC with immature stroma (P < .001), strong α-SMA expression (P = .005), non-steatotic tumors and non-fibrolamellar-HCC (P < .001). Additionally, tumor budding was related to both anti- and pro-tumor immune responses. Patients were classified into immune type A and immune type B according to the immune score. Based on tumor budding grade and immunotype, patients were classified into four subgroups: ISA-TBhigh (type I), ISB-TBhigh (type II), ISA-TBlow (type III) and ISB-TBlow (type IV). Patients with type III tumor had the best OS and DFS, whereas OS and DFS were the worst for cases with type II tumor. TP53 mutation was more frequent in IS-TB type I (ISATBhigh) patients, while IS-TB type IV (ISBTBlow) harbored high number of CTNNB1 mutation. Conclusion: Tumor-immune cell interactions in HCC is heterogeneous. HCC classification based on tumor budding and immune score correlates with patient survival and molecular alterations. The defined subtypes may have significance for utilizing individualized treatment in patients with HCC.

中文翻译：

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基于肿瘤发芽和免疫评分的肝细胞癌患者分类。

背景：在肝细胞癌（HCC）中，免疫分析和肿瘤萌发的作用仍然未知。本研究评估了HCC中肿瘤萌发与淋巴细胞浸润之间的关系。同时，根据肿瘤发芽等级和免疫评分对HCC患者进行分层。患者和方法：总共423例HCC患者分为训练（n = 212）和验证（n = 211）队列。来自切除的HCC样品的肿瘤载玻片用于肿瘤萌芽评估。基于11种免疫标记中的5种类型的免疫细胞，开发了与预后相关的免疫评分。建立了基于肿瘤发芽等级和免疫类型的分类（IS-TB类型）。为了探索IS-TB类型与肝癌分子改变的关系，通过全外显子组测序研究了100例患者的100例HCC样本和邻近的非肿瘤组织。结果：在训练和验证队列中，肿瘤萌发都是OS和DFS的独立不良预后因素（所有P值<.05）。伴有不成熟基质的肝癌中高级别的肿瘤出芽率（P <.001），强α-SMA表达（P = .005），非脂肪变性肿瘤和非纤维状HCC（P <.001） ）。另外，肿瘤出芽与抗和免疫前免疫反应均相关。根据免疫评分将患者分为免疫A型和免疫B型。根据肿瘤发芽等级和免疫类型，将患者分为四个亚组：ISA-TBhigh（I型），ISB-TBhigh（II型），ISA-TBlow（III型）和ISB-TBlow（IV型）。III型肿瘤患者的OS和DFS最好，而II型肿瘤患者的OS和DFS最差。TP53突变在IS-TB I型（ISATBhigh）患者中更为频繁，而IS-TB IV型（ISBTBlow）则携带大量CTNNB1突变。结论：肝癌中的肿瘤免疫细胞相互作用是异质的。基于肿瘤发芽和免疫评分的HCC分类与患者生存率和分子改变相关。所定义的亚型对于肝癌患者的个体化治疗可能具有重要意义。基于肿瘤发芽和免疫评分的HCC分类与患者生存率和分子改变相关。所定义的亚型对于肝癌患者的个体化治疗可能具有重要意义。基于肿瘤发芽和免疫评分的HCC分类与患者生存率和分子改变相关。所定义的亚型对于肝癌患者的个体化治疗可能具有重要意义。