Hypoxic Characteristic in the Immunosuppressive Microenvironment of Hepatocellular Carcinoma.
Hypoxic Characteristic in the Immunosuppressive Microenvironment of Hepatocellular Carcinoma.
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肝细胞癌免疫抑制微环境的缺氧特征
DOI：
10.3389/fimmu.2021.611058
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发表时间：
2021
影响因子：
7.3
通讯作者：
Zhang S
中科院分区：
文献类型：
--
作者：
Mo Z;Liu D;Rong D;Zhang S
背景：通常，肝细胞癌（HCC）存在于免疫抑制的微环境中，促进肿瘤逃避。缺氧可影响肿瘤微环境中的细胞间串扰。本研究旨在探讨和阐明肝癌患者缺氧与免疫治疗之间的潜在关系。研究方法：HCC基因组和临床病理学数据集获自癌症基因组图谱（TCGA-LIHC）、基因表达综合数据库（GSE 14520）和国际癌症基因组联盟（ICGC-LIRI）。基于单样本基因集富集分析和系统聚类将TCGA-LIHC病例进行聚类。在确定具有不同缺氧条件的免疫抑制微环境的患者后，研究了免疫特征与缺氧簇之间的相关性。随后，通过差异表达、单变量考克斯回归和套索回归分析建立缺氧相关评分。通过生存率和受试者工作特征曲线分析验证评分。GSE 14520队列用于验证免疫细胞浸润和免疫检查点表达的发现，而ICGC-LIRI队列用于验证缺氧相关评分。结果：我们发现缺氧患者免疫抑制肝癌。该簇在TCGA组群中表现出更高的免疫细胞浸润和免疫检查点表达，而在GEO组群中观察到类似的显著差异。缺氧相关评分由5个基因组成（肝配蛋白A3、二氢嘧啶酶样4、溶质载体家族2成员5、斯钙素2和赖氨酰氧化酶）。在两个队列中，生存分析显示高风险组和低风险组之间存在显著差异。此外，与其他临床参数相比，在两个队列中，已建立的评分在3年和5年时具有最高的预测性能。结论：本研究为肝癌患者体内缺氧信号与免疫抑制之间的联系提供了进一步的证据。定义缺氧相关的HCC亚型可能有助于揭示缺氧和免疫抑制微环境之间的潜在调节机制，我们的缺氧相关评分可能对未来的预测模型具有潜在意义。
Background: Generally, hepatocellular carcinoma (HCC) exists in an immunosuppressive microenvironment that promotes tumor evasion. Hypoxia can impact intercellular crosstalk in the tumor microenvironment. This study aimed to explore and elucidate the underlying relationship between hypoxia and immunotherapy in patients with HCC. Methods: HCC genomic and clinicopathological datasets were obtained from The Cancer Genome Atlas (TCGA-LIHC), Gene Expression Omnibus databases (GSE14520) and International Cancer Genome Consortium (ICGC-LIRI). The TCGA-LIHC cases were divided into clusters based on single sample gene set enrichment analysis and hierarchical clustering. After identifying patients with immunosuppressive microenvironment with different hypoxic conditions, correlations between immunological characteristics and hypoxia clusters were investigated. Subsequently, a hypoxia-associated score was established by differential expression, univariable Cox regression, and lasso regression analyses. The score was verified by survival and receiver operating characteristic curve analyses. The GSE14520 cohort was used to validate the findings of immune cell infiltration and immune checkpoints expression, while the ICGC-LIRI cohort was employed to verify the hypoxia-associated score. Results: We identified hypoxic patients with immunosuppressive HCC. This cluster exhibited higher immune cell infiltration and immune checkpoint expression in the TCGA cohort, while similar significant differences were observed in the GEO cohort. The hypoxia-associated score was composed of five genes (ephrin A3, dihydropyrimidinase like 4, solute carrier family 2 member 5, stanniocalcin 2, and lysyl oxidase). In both two cohorts, survival analysis revealed significant differences between the high-risk and low-risk groups. In addition, compared to other clinical parameters, the established score had the highest predictive performance at both 3 and 5 years in two cohorts. Conclusion: This study provides further evidence of the link between hypoxic signals in patients and immunosuppression in HCC. Defining hypoxia-associated HCC subtypes may help reveal potential regulatory mechanisms between hypoxia and the immunosuppressive microenvironment, and our hypoxia-associated score could exhibit potential implications for future predictive models.
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影响因子：
3.7
作者：
Witten DM;Tibshirani R
通讯作者：
Tibshirani R
影响因子：
32.4
作者：
Palazon, Asis;Goldrath, Ananda W.;Nizet, Victor;Johnson, Randall S.
通讯作者：
Johnson, Randall S.
影响因子：
13.8
作者：
Semenza GL
通讯作者：
Semenza GL
DOI：
10.1002/hep.31416
发表时间：
2021-01
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Ilyas SI;Wang J;El-Khoueiry AB
通讯作者：
El-Khoueiry AB
影响因子：
7
作者：
Veglia F;Gabrilovich DI
通讯作者：
Gabrilovich DI