A novel immune classification reveals distinct immune escape mechanism and genomic alterations: implications for immunotherapy in hepatocellular carcinoma.
A novel immune classification reveals distinct immune escape mechanism and genomic alterations: implications for immunotherapy in hepatocellular carcinoma.
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DOI：
10.1186/s12967-020-02697-y
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发表时间：
2021-01-06
影响因子：
7.4
通讯作者：
Han X
中科院分区：
文献类型：
--
作者：
Liu Z;Zhang Y;Shi C;Zhou X;Xu K;Jiao D;Sun Z;Han X
肿瘤免疫微环境（TIME）对预后和免疫治疗有重要影响。然而，异质性时间和时间影响免疫治疗的机制尚未阐明在肝细胞癌（HCC）。从TCGA和GEO数据库中共收集了2195例符合条件的HCC患者。我们综合探讨不同异质性TIME表型及其临床意义。进一步研究了潜在的免疫逃逸机制和可能驱动不同表型形成的基因组改变。我们在HCC中鉴定了三种表型：TIME-1，“免疫缺陷”表型，具有免疫细胞耗竭和增殖; TIME-2，“免疫抑制”表型，具有免疫抑制细胞富集; TIME-3，“免疫激活表型”，具有丰富的白细胞浸润和免疫激活。三种表型的预后和对索拉非尼和免疫治疗的敏感性不同。我们还强调了潜在的免疫逃逸机制：在TIME-1中缺乏白细胞和有缺陷的肿瘤抗原呈递能力，在TIME-2中增加免疫抑制细胞，在TIME-3中富含免疫抑制分子。不同的表型也显示了特定的基因组事件：TIME-1以TP 53、CDKN 2A、CTNNB 1、AXIN 1和FOXD 4改变为特征; TIME-2以PI 3 K通路中的显著改变模式为特征; TIME-3以ARID 1A突变为特征。此外，TIME指数（TI）被提出来量化TIME浸润模式，它是一个上级预后和免疫治疗的预测。开发了一个管道，将单个患者分类为这三种亚型之一，并计算TI。我们确定了三种具有不同临床结局、免疫逃逸机制和HCC基因组改变的TIME表型，这可能为提高免疫治疗的疗效提供策略。TI作为一种新的预后和免疫标志物，可以指导HCC的个性化免疫治疗和临床管理。
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). 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. 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 characterized by ARID1A mutation. Besides, the TIME index (TI) was proposed to quantify TIME infiltration pattern, and it was a superior prognostic and immunotherapy predictor. A pipeline was developed to classify single patient into one of these three subtypes and calculated the TI. We identified three TIME phenotypes with different clinical outcomes, immune escape mechanisms and genomic alterations in HCC, which could present strategies for improving the efficacy of immunotherapy. TI as a novel prognostic and immunotherapeutic signature that could guide personalized immunotherapy and clinical management of HCC.
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影响因子：
12.3
作者：
Blokzijl F;Janssen R;van Boxtel R;Cuppen E
通讯作者：
Cuppen E
影响因子：
5.7
作者：
Honda S;Minato M;Suzuki H;Fujiyoshi M;Miyagi H;Haruta M;Kaneko Y;Hatanaka KC;Hiyama E;Kamijo T;Okada T;Taketomi A
通讯作者：
Taketomi A
影响因子：
--
作者：
Ghouri YA;Mian I;Rowe JH
通讯作者：
Rowe JH
影响因子：
3.7
作者：
Hoshida Y;Brunet JP;Tamayo P;Golub TR;Mesirov JP
通讯作者：
Mesirov JP
影响因子：
158.5
作者：
Finn, Richard S.;Qin, Shukui;Cheng, Ann-Lii
通讯作者：
Cheng, Ann-Lii