Hypoxia-Adenosinergic Immunosuppression: Tumor Protection by T Regulatory Cells and Cancerous Tissue Hypoxia
Hypoxia-Adenosinergic Immunosuppression: Tumor Protection by T Regulatory Cells and Cancerous Tissue Hypoxia
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DOI：
10.1158/1078-0432.ccr-08-0229
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发表时间：
2008-10-01
影响因子：
11.5
通讯作者：
Ohta, Akio
中科院分区：
文献类型：
--
作者：
Sitkovsky, Michail V.;Kjaergaard, Jorgen;Ohta, Akio
癌组织免受肿瘤识别 CD8+ 和 CD4+ T 细胞（抗肿瘤 T 细胞）的保护限制了免疫疗法的治疗潜力。我们认为，肿瘤保护在很大程度上归因于（a）局部肿瘤微环境中缺氧驱动的细胞外腺苷积累对抗肿瘤T细胞的抑制，以及（b）T调节细胞产生的细胞外腺苷。腺苷通过抗肿瘤 T 细胞上的细胞内环 AMP 升高 A2A 腺苷受体 (A2AR) 触发免疫抑制信号传导。此外，缺氧肿瘤微环境中激活的抗肿瘤T细胞可以被免疫抑制缺氧诱导因子1α水平升高所抑制。当 A2AR 被基因消除或用合成药物或天然 A2AR 拮抗剂 1, 3,7-三甲基黄嘌呤（咖啡因）拮抗时，观察到完全排斥或肿瘤生长迟缓。有前途的策略可能是将抗缺氧腺苷能治疗与靶向其他负调节因子（例如 CTL 抗原 4 阻断）相结合，以防止肿瘤产生的腺苷和 T 调节细胞产生的腺苷对抗肿瘤 T 细胞的抑制。对小鼠肿瘤排斥反应的观察和大量前瞻性流行病学研究支持抗缺氧-腺苷能联合免疫治疗的可行性。
Cancerous tissue protection from tumor-recognizing CD8(+) and CD4(+) T cells (antitumor T cells) limits the therapeutic potential of immunotherapies. We propose that tumor protection is to a large extent due to (a) inhibition of antitumor T cells by hypoxia-driven accumulation of extracellular adenosine in local tumor microenvironment and due to (b) T regulatory cell-produced extracellular adenosine. The adenosine triggers the immunosuppressive signaling via intracellular cyclic AMP-elevating A2A adenosine receptors (A2AR) on antitumor T cells. In addition, the activated antitumor T cells in hypoxic tumor microenvironment could be inhibited by elevated levels of immunosuppressive hypoxia-inducible factor-1 alpha. Complete rejection or tumor growth retardation was observed when A2AR has been genetically eliminated or antagonized with synthetic drug or with natural A2AR antagonist 1, 3,7-trimethylxanthine (caffeine). The promising strategy may be in combining the anti-hypoxia-adenosinergic treatment that prevents inhibition of antitumor T cells by tumor-produced and T regulatory cell-produced adenosine with targeting of other negative regulators, such as CTL antigen-4 blockade. Observations of tumor rejection in mice and massive prospective epidemiologic studies support the feasibility of anti-hypoxia-adenosinergic combined immunotherapy.