Targeting the hypoxia-adenosinergic signaling pathway to improve the adoptive immunotherapy of cancer.
Targeting the hypoxia-adenosinergic signaling pathway to improve the adoptive immunotherapy of cancer.
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DOI：
10.1007/s00109-013-1001-9
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发表时间：
2013-02
影响因子：
4.7
通讯作者：
Ohta, Akio
中科院分区：
文献类型：
--
作者：
Sitkovsky, Michail;Ohta, Akio
关键词：
FDA最近批准了阻断免疫负调节剂的癌症疫苗和药物，进一步提高了对癌症免疫治疗的有希望方法的兴趣。然而，令人不安的短寿命延长也强调了需要更好地理解即使在免疫负调节剂阻断后也能防止肿瘤排斥和存活的机制。在这里，我们描述了“代谢为基础的”免疫抑制机制的影响，其中局部组织缺氧驱动的细胞外腺苷的积累通过激活的免疫细胞表面上的A2腺苷受体触发抑制。该分子途径在炎症和癌性组织微环境中的免疫抑制机制中至关重要。肿瘤产生的细胞外腺苷和A2腺苷受体对肿瘤的保护可能是正常组织保护机制的错误应用，该机制限制了抗病原体免疫反应期间对重要器官的过度附带损伤。关于细胞外腺苷的免疫抑制作用的现有技术的概述之后是研究的历史观点，其集中于阐明保护重要器官的组织免受过度附带损伤的生理负调节剂，但是作为权衡，也可能削弱抗病原体效应子功能并否定抗肿瘤免疫细胞破坏癌细胞的尝试。
The recent approval by the FDA of cancer vaccines and drugs that blockade immunological negative regulators has further enhanced interest in promising approaches of the immunotherapy of cancer. However, the disappointingly short life extension has also underscored the need to better understand the mechanisms that prevent tumor rejection and survival even after the blockade of immunological negative regulators. Here, we describe the implications of the “metabolism-based” immunosuppressive mechanism, where the local tissue hypoxia-driven accumulation of extracellular adenosine triggers suppression via A2 adenosine receptors on the surface of activated immune cells. This molecular pathway is of critical importance in mechanisms of immunosuppression in inflamed and cancerous tissue microenvironments. The protection of tumors by tumor-generated extracellular adenosine and A2 adenosine receptors could be the misguided application of the normal tissue-protecting mechanism that limits excessive collateral damage to vital organs during the anti-pathogen immune response. The overview of the current state of the art regarding the immunosuppressive effects of extracellular adenosine is followed by an historical perspective of studies focused on the elucidation of the physiological negative regulators that protect tissues of vital organs from excessive collateral damage, but, as a trade-off, may also weaken the anti-pathogen effector functions and negate the attempts of anti-tumor immune cells to destroy cancerous cells.
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影响因子：
3.7
作者：
Fredholm BB
通讯作者：
Fredholm BB
影响因子：
3.5
作者：
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影响因子：
6.7
作者：
Fredholm, Bertil B.;Chern, Yijuang;Sitkovsky, Michail
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Sitkovsky, Michail
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作者：
Cadieux, JS;Leclerc, P;Pouliot, M
通讯作者：
Pouliot, M
影响因子：
50.3
作者：
Drake, CG;Doody, ADH;Adler, AJ
通讯作者：
Adler, AJ