HIF1Aexpression correlates with increased tumor immune and stromal signatures and aggressive phenotypes in human cancers
HIF1Aexpression correlates with increased tumor immune and stromal signatures and aggressive phenotypes in human cancers
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DOI：
10.1007/s13402-020-00534-4
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发表时间：
2020-06-01
影响因子：
6.6
通讯作者：
Wang, Xiaosheng
中科院分区：
文献类型：
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作者：
Chen, Baotao;Li, Lin;Wang, Xiaosheng
背景尽管许多研究已经揭示了HIF 1A（缺氧诱导因子1 α亚基）在调节与癌症发展相关的各种途径中的重要作用，但缺乏对HIF 1A表达与肿瘤免疫、肿瘤微环境和泛癌中其他肿瘤表型之间关系的系统研究。方法利用来自癌症基因组图谱（TCGA）项目的10个癌症队列的癌症基因组学数据集，我们研究了HIF 1A表达与肿瘤免疫和间质特征以及各种肿瘤表型（包括细胞增殖、干性、上皮-间质转化（EMT）、肿瘤纯度、致癌信号传导和临床结局）的相关性。结果HIF-1表达上调与多种肿瘤的免疫和间质特征增强、侵袭性表型和生存率降低相关。此外，HIF 1的上调不仅与多种致癌信号通路的激活有关，而且还与肿瘤抑制信号的增加有关，包括细胞凋亡和抗肿瘤免疫应答，表明HIF 1A在癌症发展中的双重作用。然而，HIF 1A表达与免疫抑制信号的相关性比与免疫促进信号的相关性更强。此外，发现HIF 1A表达与肿瘤免疫浸润和PD-L1表达呈正相关，表明HIF 1A表达升高的肿瘤可能表现出更积极的免疫治疗反应。该适应症在接受抗PD-1/PD-L1免疫治疗的肾癌队列中得到证实。结论HIF-1表达上调与肿瘤免疫和间质特征的增加以及人类肿瘤侵袭性表型相关。我们的分析可能为HIF 1A在肿瘤生物学和临床管理中的作用提供新的见解。
Background Although many studies have revealed essential roles of HIF1A (hypoxia inducible factor 1 subunit alpha) in regulating various pathways associated with cancer development, a systematic investigation of associations ofHIF1Aexpression with tumor immunity, the tumor microenvironment and other tumor phenotypes in pan-cancer is lacking. Methods Using cancer genomics datasets of 10 cancer cohorts from the Cancer Genome Atlas (TCGA) program, we investigated associations ofHIF1Aexpression with tumor immune and stromal signatures, and various tumor phenotypes, including cell proliferation, stemness, epithelial-mesenchymal transition (EMT), tumor purity, oncogenic signaling, and clinical outcomes. Results HIF1Aupregulation was found to be associated with increased immune and stromal signatures, aggressive phenotypes, and worse survival rates in various cancers. Moreover,HIF1Aupregulation was not only associated with activation of various oncogenic signaling pathways, but also with increased tumor suppressive signatures, including apoptosis and anti-tumor immune response, indicative of a dual role ofHIF1Ain cancer development. However,HIF1Aexpression showed a stronger correlation with immune-inhibiting signatures than with immune-promoting signatures. Furthermore,HIF1Aexpression was found to be positively associated with both tumor immune infiltration and PD-L1 expression, indicating that tumors with elevated expression ofHIF1Amay exhibit a more active immunotherapy response. This indication was substantiated in a kidney cancer cohort receiving anti-PD-1/PD-L1 immunotherapy. Conclusions HIF1Aupregulation correlates with increased tumor immune and stromal signatures and aggressive phenotypes in human cancers. Our analysis may provide new insights into the role ofHIF1Ain tumor biology and clinical management.