A classification based on tumor budding and immune score for patients with hepatocellular carcinoma
A classification based on tumor budding and immune score for patients with hepatocellular carcinoma
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基于肿瘤出芽和免疫评分的肝细胞癌患者分类
DOI：
10.1080/2162402x.2019.1672495
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发表时间：
2019-11-08
期刊：
影响因子：
7.2
通讯作者：
Zhang Yange
中科院分区：
文献类型：
--
作者：
Li Wei;Zhang Delin;Zhang Yange
摘要背景：免疫谱和肿瘤出芽在肝细胞癌（HCC）中的作用在很大程度上仍不清楚。本研究评估了HCC中肿瘤出芽和淋巴细胞浸润之间的关系。同时，HCC患者根据肿瘤出芽等级和免疫评分进行分层。患者和方法：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出芽评估。基于11种免疫标志物中的5种类型的免疫细胞，开发了一种与肿瘤相关的免疫评分。建立了基于肿瘤出芽等级和免疫类型的分类（IS-TB型）。为探讨IS-TB分型与HCC分子变异的关系，采用全外显子组测序技术对100例HCC患者及其癌旁组织进行了研究。结果：在训练组和验证组中，肿瘤出芽是OS和DFS的独立不良预后因素（所有P值均<0.05）。在间质不成熟的HCC（P < .001）、α-SMA强表达的HCC（P = .005）、非脂肪化肿瘤和非纤维板层型HCC（P < .001）中，高级别肿瘤出芽率显著较高。此外，肿瘤出芽与抗肿瘤和促肿瘤免疫应答相关。根据免疫评分将患者分为免疫A型和免疫B型。根据肿瘤出芽分级和免疫分型，将患者分为4个亚组：ISA-TB高（I型）、ISB-TB高（II型）、ISA-TB低（III型）和ISB-TB低（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。TP 53突变在I型IS-TB（ISATBhigh）患者中更常见，而IV型IS-TB（ISBTBlow）则具有大量CTNNB 1突变。结论：HCC中肿瘤-免疫细胞相互作用是异质性的。基于肿瘤出芽和免疫评分的HCC分类与患者生存和分子改变相关。确定的亚型可能对HCC患者的个体化治疗具有重要意义。
ABSTRACT 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.