Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Nature. 2011 Jul 13;475(7355):226-30. doi: 10.1038/nature10169.
Although immune mechanisms can suppress tumour growth, tumours establish potent, overlapping mechanisms that mediate immune evasion. Emerging evidence suggests a link between angiogenesis and the tolerance of tumours to immune mechanisms. Hypoxia, a condition that is known to drive angiogenesis in tumours, results in the release of damage-associated pattern molecules, which can trigger the rejection of tumours by the immune system. Thus, the counter-activation of tolerance mechanisms at the site of tumour hypoxia would be a crucial condition for maintaining the immunological escape of tumours. However, a direct link between tumour hypoxia and tolerance through the recruitment of regulatory cells has not been established. We proposed that tumour hypoxia induces the expression of chemotactic factors that promote tolerance. Here we show that tumour hypoxia promotes the recruitment of regulatory T (T(reg)) cells through induction of expression of the chemokine CC-chemokine ligand 28 (CCL28), which, in turn, promotes tumour tolerance and angiogenesis. Thus, peripheral immune tolerance and angiogenesis programs are closely connected and cooperate to sustain tumour growth.
尽管免疫机制可以抑制肿瘤生长，但肿瘤会建立强大的、重叠的机制来介导免疫逃逸。新出现的证据表明血管生成与肿瘤对免疫机制的耐受性之间存在联系。众所周知，缺氧会导致肿瘤中的血管生成，从而导致损伤相关模式分子的释放，这些分子可以触发免疫系统对肿瘤的排斥。因此，在肿瘤缺氧部位逆转耐受机制对于维持肿瘤的免疫逃逸至关重要。然而，肿瘤缺氧与通过招募调节细胞的耐受之间的直接联系尚未建立。我们提出，肿瘤缺氧诱导趋化因子的表达，从而促进耐受。在这里，我们表明肿瘤缺氧通过诱导趋化因子 CC-趋化因子配体 28（CCL28）的表达促进调节性 T（Treg）细胞的募集，进而促进肿瘤耐受和血管生成。因此，外周免疫耐受和血管生成程序密切相关并协同维持肿瘤生长。
