A novel immune classification reveals distinct immune escape mechanism and genomic alterations: implications for immunotherapy in hepatocellular carcinoma

作者：Zaoqu Liu, Yuyuan Zhang, Chengcheng Shi, Xueliang Zhou, Kaihao Xu, Dechao Jiao, Zhenqiang Sun, Xinwei Han · 发表于：Journal of Translational Medicine · 年份：2021 · DOI：10.1186/s12967-020-02697-y · 被引用次数：122 · 研究领域：Cancer Immunotherapy and Biomarkers、Ferroptosis and cancer prognosis、Hepatocellular Carcinoma Treatment and Prognosis

BACKGROUND: The tumor immunological microenvironment (TIME) has a prominent impact on prognosis and immunotherapy. However, the heterogeneous TIME and the mechanisms by which TIME affects immunotherapy have not been elucidated in hepatocellular carcinoma (HCC). METHODS: A total of 2195 eligible HCC patients from TCGA and GEO database were collected. We comprehensively explored the different heterogeneous TIME phenotypes and its clinical significance. The potential immune escape mechanisms and what genomic alterations may drive the formation of different phenotypes were further investigated. RESULTS: We identified three phenotypes in HCC: TIME-1, the "immune-deficiency" phenotype, with immune cell depletion and proliferation; TIME-2, the "immune-suppressed" phenotype, with enrichment of immunosuppressive cells; TIME-3, the "immune-activated phenotype", with abundant leukocytes infiltration and immune activation. The prognosis and sensitivity to both sorafenib and immunotherapy differed among the three phenotypes. We also underlined the potential immune escape mechanisms: lack of leukocytes and defective tumor antigen presentation capacity in TIME-1, increased immunosuppressive cells in TIME-2, and rich in immunoinhibitory molecules in TIME-3. The different phenotypes also demonstrated specific genomic events: TIME-1 characterized by TP53, CDKN2A, CTNNB1, AXIN1 and FOXD4 alterations; TIME-2 characterized by significant alteration patterns in the PI3K pathway; TIME-3 characteriz...