Multi-omics Analysis of Microenvironment Characteristics and Immune Escape Mechanisms of Hepatocellular Carcinoma
Multi-omics Analysis of Microenvironment Characteristics and Immune Escape Mechanisms of Hepatocellular Carcinoma
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DOI：
10.3389/fonc.2019.01019
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发表时间：
2019-10-15
影响因子：
4.7
通讯作者：
Liu, Jun
中科院分区：
文献类型：
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作者：
Li, Wenli;Wang, Huimei;Liu, Jun
原发性肿瘤的免疫环境对免疫治疗有着深远的影响。然而，免疫环境在肝细胞癌（HCC）中的临床相关性在很大程度上是未知的。在这里，免疫概况和其在肝癌的临床反应进行了研究。在本研究中使用了来自三个队列（癌症基因组图谱，TCGA，n = 257;基因表达综合体，GEO，n = 170;国际癌症基因组联盟，ICGC，n = 142）的569个HCC的基因表达谱。在I/II期HCC中鉴定了负责全局免疫基因的五种基因表达亚型（C1-C5）。发现在大多数多基因中，亚型C4与免疫谱的上调相关，亚型C5与免疫谱的下调相关。免疫相关性分析显示，C3和C4亚型的免疫评分较高，预后较好。TP 53、CTNNB 1和AXIN 1基因突变频率在5个亚组间差异有统计学意义。此外，与其他亚型相比，C4亚型中PDCD 1、CD 274、PDCD 1 LG 2、CTLA 4、CD 86和CD 80的表达更高。5种亚型免疫相关基因的WGCNA显示，蓝色和青绿色模块与C4亚型正相关，与KEGG数据库中的12条共同通路相关。这些结果在来自NCI（国家癌症研究所）队列（GSE 14520）和ICGC（国际癌症基因组联盟）队列的外部队列中得到验证。总之，一种免疫增强亚型和一种免疫降低亚型具有不同的免疫和临床特征，可能为开发免疫系统功能障碍相关癌症的新治疗策略提供指导。
The immune environment in primary tumor has a profound impact on immunotherapy. However, the clinical relevance of immune environment in hepatocellular carcinoma (HCC) is largely unknown. Here, the immune profile and its clinical response in HCC were investigated. The gene expression profiles of 569 HCCs from three cohorts (The Cancer Genome Atlas, TCGA, n = 257; Gene Expression Omnibus, GEO, n = 170; International Cancer Genome Consortium, ICGC, n = 142) were used in the current study. Five gene expression subtypes (C1-C5) responsible for global immune genes were identified in HCCs at stage I/II. It was found that subtype C4 was associated with upregulation and subtype C5 was associated with downregulation of immune profiles in most metagenes. Immune-correlation analysis of the five subtypes demonstrated that C3 and C4 had higher immune score and better prognostic outcome, as compared with other subtypes. Moreover, the mutation frequencies of TP53, CTNNB1, and AXIN1 had significant difference in the five subgroups. Further, the expression of PDCD1, CD274, PDCD1LG2, CTLA4, CD86, and CD80 was higher in subtype C4 in comparison with the other subtypes. The WGCNA of immune-related genes in the five subtypes revealed that blue and turquoise modules were positively correlated with subtype C4 and were associated with 12 common pathways in the KEGG database. These results were validated in external cohorts from the NCI (National Cancer Institute) cohort (GSE14520) and the ICGC (International Cancer Genome Consortium) cohort. In summary, one immune-enhanced subtype and one immune-decreased subtype having different immune and clinical characteristics may provide guidance for developing novel treatment strategies for immune system malfunction-related cancer.