缺氧-腺苷免疫抑制：调节T细胞和肿瘤组织缺氧产生的肿瘤保护

Hypoxia-Adenosinergic Immunosuppression: Tumor Protection by T Regulatory Cells and Cancerous Tissue Hypoxia

肿瘤识别CD8(+)和CD4(+)T细胞产生的癌组织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是由于

(a)    在局部肿瘤微环境中缺氧驱动的细胞外腺苷聚集导致对抗肿瘤T细胞的抑制

(b)   调节T细胞产生的细胞外腺苷。腺苷通过细胞内升高C-amp的A2A腺苷受体（A2AR）触发给抗肿瘤T细胞的免疫抑制信号。

此外，缺氧微环境中激活的抗肿瘤T细胞可被升高的缺氧诱导因子1alpha（HIF-1alpha）抑制。当A2AR被基因改造敲除或被合成药物拮抗或被天然拮抗物咖啡因拮抗时，观察到肿瘤被完全排斥或生长迟缓。

有希望的策略可能是将抗缺氧-腺苷酸的治疗结合起来，以防止肿瘤和调控T细胞产生的腺苷的对抗肿瘤T细胞的抑制作用，并针对其他的消极调控因子，如CTL抗原-4阻断。

对小鼠肿瘤排斥的观察和大量的前瞻性流行病学研究支持抗低氧-腺苷联合免疫疗法的可行性。

参考文献：

T调控细胞（Treg）分泌的腺苷免疫抑制肿瘤保护和肿瘤组织的缺氧

Hypoxia-Adenosinergic Immunosuppression: Tumor Protection by T Regulatory Cells and Cancerous Tissue Hypoxia.

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-1alpha. 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.

https://www.researchgate.net/publication/23294134_Hypoxia-Adenosinergic_Immunosuppression_Tumor_Protection_by_T_Regulatory_Cells_and_Cancerous_Tissue_Hypoxia [accessed Jul 23, 2017].