Palazon Asis, Tyrakis Petros A, Macias David, Veliça Pedro, Rundqvist Helene, Fitzpatrick Susan, Vojnovic Nikola, Phan Anthony T, Loman Niklas, Hedenfalk Ingrid, Hatschek Thomas, Lövrot John, Foukakis Theodoros, Goldrath Ananda W, Bergh Jonas, Johnson Randall S
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK; Cancer Research UK, Cambridge Institute, Cambridge CB2 0RE, UK.
Cancer Cell. 2017 Nov 13;32(5):669-683.e5. doi: 10.1016/j.ccell.2017.10.003.
Cytotoxic T cells infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found that HIF-1α, but not HIF-2α, was essential for the effector state in CD8 T cells. Furthermore, loss of HIF-1α in CD8 T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization. Deletion of VEGF-A, an HIF target gene, in CD8 T cells accelerated tumorigenesis while also altering vascularization. Analyses of human breast cancer showed inverse correlations between VEGF-A expression and CD8 T cell infiltration, and a link between T cell infiltration and vascularization. These data demonstrate that the HIF-1α/VEGF-A axis is an essential aspect of tumor immunity.
浸润肿瘤的细胞毒性T细胞被认为在适应缺氧肿瘤微环境的过程中会利用缺氧诱导因子（HIF）转录因子。对两种关键HIF异构体的缺失分析发现，HIF-1α而非HIF-2α对CD8 T细胞的效应状态至关重要。此外，CD8 T细胞中HIF-1α的缺失减少了肿瘤浸润和肿瘤细胞杀伤，并改变了肿瘤血管生成。CD8 T细胞中HIF靶基因VEGF-A的缺失加速了肿瘤发生，同时也改变了血管生成。对人类乳腺癌的分析表明，VEGF-A表达与CD8 T细胞浸润呈负相关，且T细胞浸润与血管生成之间存在联系。这些数据表明，HIF-1α/VEGF-A轴是肿瘤免疫的一个重要方面。
