Lukashev D, Ohta A, Sitkovsky M
New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, 113 Mugar, Boston, MA 02115, USA.
Cancer Metastasis Rev. 2007 Jun;26(2):273-9. doi: 10.1007/s10555-007-9054-2.
The evolutionarily selected tissue-protecting mechanisms are likely to be triggered by an event of universal significance for all surrounding cells. Such an event could be damage to blood vessels, which would result in local tissue hypoxia. It is now recognized that tissue hypoxia can initiate the tissue-protecting mechanism mediated by at least two different biochemical pathways. The central message of this review is that tumor cells are protected from immune damage in hypoxic and immunosuppressive tumor microenvironments due to the inactivation of anti-tumor T cells by the combined action of these two hypoxia-driven mechanisms. Firstly, tumor hypoxia-produced extracellular adenosine inhibits anti-tumor T cells via their G(s)-protein-coupled and cAMP-elevating A2A and A2B adenosine receptors (A2AR/A2BR). Levels of extracellular adenosine are increased in tumor microenvironments due to the changes in activities of enzymes involved in adenosine metabolism. Secondly, TCR-activated and/or tumor hypoxia-exposed anti-tumor T cells may be inhibited in tumor microenvironments by Hypoxia-inducible Factor 1alpha (HIF-1alpha) Hence, HIF-1alpha activity in T cells may contribute to the tumor-protecting immunosuppressive effects of tumor hypoxia. Here, we summarize the data that support the view that protection of hypoxic cancerous tissues from anti-tumor T cells is mediated by the same mechanism that protects normal tissues from the excessive collateral damage by overactive immune cells during acute inflammation.
进化选择的组织保护机制可能由对所有周围细胞具有普遍意义的事件触发。这样的事件可能是血管损伤，这会导致局部组织缺氧。现在人们认识到，组织缺氧可通过至少两种不同的生化途径启动组织保护机制。本综述的核心观点是，在缺氧和免疫抑制的肿瘤微环境中，肿瘤细胞受到保护免受免疫损伤，这是由于这两种缺氧驱动机制的联合作用使抗肿瘤T细胞失活。首先，肿瘤缺氧产生的细胞外腺苷通过其G(s)蛋白偶联且能升高cAMP的A2A和A2B腺苷受体（A2AR/A2BR）抑制抗肿瘤T细胞。由于参与腺苷代谢的酶活性发生变化，肿瘤微环境中的细胞外腺苷水平升高。其次，TCR激活的和/或暴露于肿瘤缺氧环境的抗肿瘤T细胞在肿瘤微环境中可能会被缺氧诱导因子1α（HIF-1α）抑制。因此，T细胞中的HIF-1α活性可能有助于肿瘤缺氧的肿瘤保护免疫抑制作用。在此，我们总结了支持以下观点的数据：缺氧癌组织免受抗肿瘤T细胞攻击的保护作用是由一种机制介导的，该机制在急性炎症期间保护正常组织免受过度活跃的免疫细胞造成的过度附带损伤。
