Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Front Immunol. 2021 Feb 17;12:611058. doi: 10.3389/fimmu.2021.611058. eCollection 2021.
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. 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. 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. 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.
一般来说，肝细胞癌（HCC）存在于促进肿瘤逃逸的免疫抑制微环境中。缺氧会影响肿瘤微环境中的细胞间通讯。本研究旨在探讨和阐明 HCC 患者中缺氧与免疫治疗之间的潜在关系。从癌症基因组图谱（TCGA-LIHC）、基因表达综合数据库（GSE14520）和国际癌症基因组联合会（ICGC-LIRI）获得 HCC 基因组和临床病理数据集。根据单样本基因集富集分析和层次聚类，将 TCGA-LIHC 病例分为聚类。确定具有不同缺氧条件的免疫抑制微环境患者后，研究了免疫特征与缺氧聚类之间的相关性。随后，通过差异表达、单变量 Cox 回归和套索回归分析建立了一个与缺氧相关的评分。通过生存和接收者操作特征曲线分析验证了该评分。使用 GSE14520 队列验证免疫细胞浸润和免疫检查点表达的发现，使用 ICGC-LIRI 队列验证与缺氧相关的评分。我们确定了具有免疫抑制性 HCC 的缺氧患者。该聚类在 TCGA 队列中表现出更高的免疫细胞浸润和免疫检查点表达，而在 GEO 队列中也观察到类似的显著差异。缺氧相关评分由五个基因组成（ephrin 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，生存分析显示高危组和低危组之间存在显著差异。此外，与其他临床参数相比，该评分在两个队列中均在 3 年和 5 年时具有最高的预测性能。本研究进一步证明了患者缺氧信号与 HCC 免疫抑制之间的联系。定义与缺氧相关的 HCC 亚型可能有助于揭示缺氧与免疫抑制微环境之间的潜在调节机制，我们的与缺氧相关的评分可能对未来的预测模型具有潜在意义。
