Gene transfer of antisense hypoxia inducible factor-1 α enhances the therapeutic efficacy of cancer immunotherapy
Gene transfer of antisense hypoxia inducible factor-1 α enhances the therapeutic efficacy of cancer immunotherapy
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DOI：
10.1038/sj.gt.3301388
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发表时间：
2001-04-01
期刊：
影响因子：
5.1
通讯作者：
Krissansen, GW
中科院分区：
文献类型：
--
作者：
Sun, X;Kanwar, JR;Krissansen, GW
实体瘤通过激活参与血管生成和葡萄糖代谢的多个基因来满足其对新生血管和增加糖酵解的需求，以对抗缺氧。缺氧诱导因子-1（HIF-1）是一种组成型表达的碱性螺旋-环-螺旋转录因子，由HIF-1 α和HIF-1 β（HIF-1 β）组装而成，其响应于缺氧而稳定，并在常氧条件下迅速降解。它激活了维持氧稳态的重要基因的转录。在这里，我们证明了通过肿瘤内基因转移反义HIF-1 α质粒来下调HIF-1 α，导致VEGF下调，并降低肿瘤微血管密度。反义HIF-1 α单一疗法导致小（直径0.1 cm）EL-4肿瘤的完全和永久排斥，这对于其中肿瘤生长的短暂抑制是常态的抗血管生成剂是不寻常的。它诱导NK细胞依赖性的肿瘤排斥反应，但未能刺激全身T细胞介导的抗肿瘤免疫，并与B7-1介导的免疫疗法协同作用，导致单一疗法难治的较大EL-4肿瘤（直径0.4 cm）的NK细胞和CD 8 T细胞依赖性排斥反应。通过联合治疗治愈其肿瘤的小鼠抵抗亲本肿瘤细胞的再激发，表明已经实现了全身抗肿瘤免疫。总之，尽管正在进行深入的研究以靶向许多HIF-1效应物，但本文的结果表明，通过靶向HIF-1本身来阻断缺氧诱导途径和增强NK介导的抗肿瘤免疫可能是有利的，特别是当与癌症免疫疗法组合时。
Solid tumors meet their demands for nascent blood vessels and increased glycolysis, to combat hypoxia, by activating multiple genes involved in angiogenesis and glucose metabolism. Hypoxia inducible factor-1 (HIF-1) is a constitutively expressed basic helix-loop-helix transcription factor, formed by the assembly of HIF-1 alpha and HIF-1 beta (Amt), that is stabilized in response to hypoxia, and rapidly degraded under normoxic conditions. It activates the transcription of genes important for maintaining oxygen homeostasis. Here, we demonstrate that engineered down-regulation of HIF-1 alpha by intratumoral gene transfer of an antisense HIF-1 alpha plasmid leads to the down-regulation of VEGF, and decreased tumor microvessel density. Antisense HIF-1 alpha monotherapy resulted in the complete and permanent rejection of small (0.1 cm in diameter) EL-4 tumors, which is unusual for an anti-angiogenic agent where transient suppression of tumor growth is the norm. It induced NK cell-dependent rejection of tumors, but failed to stimulate systemic T cell-mediated anti-tumor immunity, and synergized with B7-1-mediated immunotherapy to cause the NK cell and CD8 T cell-dependent rejection of larger EL-4 tumors (0.4 cm in diameter) that were refractory to monotherapies. Mice cured of their tumors by combination therapy resisted a rechallenge with parental tumor cells, indicating systemic antitumor immunity had been achieved. in summary, whilst intensive investigations are in progress to target the many HIF-1 effecters, the results herein indicate that blocking hypoxia-inducible pathways and enhancing NK-mediated antitumor immunity by targeting HIF-1 itself may be advantageous, especially when combined with cancer immunotherapy.