A2A adenosine receptor protects tumors from antitumor T cells
A2A adenosine receptor protects tumors from antitumor T cells
复制标题
DOI：
10.1073/pnas.0605251103
复制
发表时间：
2006-08-29
影响因子：
11.1
通讯作者：
Sitkovsky, Michail
中科院分区：
文献类型：
--
作者：
Ohta, Akio;Gorelik, Elieser;Sitkovsky, Michail
A2 A腺苷受体（A2 AR）已被证明是免疫细胞保护正常组织免受炎症损伤的关键和非冗余的负调节因子。我们假设A2 AR也通过抑制进入的抗肿瘤T淋巴细胞来保护癌组织。在这里，我们证实了这一假设，表明在宿主中A2 AR的基因缺失导致约60%的A2 AR缺陷型小鼠对已建立的免疫原性肿瘤的排斥，而在对照WT小鼠中未观察到排斥。使用拮抗剂，包括咖啡因，或通过siRNA预处理T细胞靶向A2受体，改善了抗肿瘤T细胞对肿瘤生长的抑制、对转移的破坏和对新血管形成的预防。这些数据表明，A2 AR的作用是T细胞自主的。在富含腺苷的肿瘤微环境中，抗肿瘤T细胞通过其A2 AR的抑制可以解释一些癌症患者中肿瘤和抗肿瘤免疫细胞的矛盾共存（“Hellstrom悖论”）。我们建议靶向缺氧->腺苷-> ASAR通路作为癌症免疫治疗策略，以防止肿瘤微环境中抗肿瘤T细胞的抑制。同样的策略可以防止免疫应答的过早终止，并改善疫苗诱导的抗肿瘤和抗病毒T细胞的发育。在A2 AR缺陷小鼠中黑素瘤排斥期间的自身免疫的观察表明T细胞中的A2 AR在预防自身免疫中也是重要的。因此，尽管使用缺氧->腺苷-> A2 AR途径抑制剂可以改善抗肿瘤免疫，但是通过选择性药物募集该途径预期会减弱自身免疫组织损伤。
The A2A adenosine receptor (A2AR) has been shown to be a critical and nonredundant negative regulator of immune cells in protecting normal tissues from inflammatory damage. We hypothesized that A2AR also protects cancerous tissues by inhibiting incoming antitumor T lymphocytes. Here we confirm this hypothesis by showing that genetic deletion of A2AR in the host resulted in rejection of established immunogenic tumors in approximate to 60% of A2AR-deficient mice with no rejection observed in control WT mice. The use of antagonists, including caffeine, or targeting the A2 receptors by siRNA pretreatment of T cells improved the inhibition of tumor growth, destruction of metastases, and prevention of neovascularization by antitumor T cells. The data suggest that effects of A2AR are T cell autonomous. The inhibition of antitumor T cells via their A2AR in the adenosine-rich tumor microenvironment may explain the paradoxical coexistence of tumors and antitumor immune cells in some cancer patients (the "Hellstrom paradox"). We propose to target the hypoxia -> adenosine -> ASAR pathway as a cancer immumotherapy strategy to prevent the inhibition of antitumor T cells in the tumor microenvironment. The same strategy may prevent the premature termination of immune response and improve the vaccine-induced development of antitumor and antiviral T cells. The observations of autoimmunity during melanoma rejection in A2AR-deficient mice suggest that A2AR in T cells is also important in preventing autoimmunity. Thus, although using the hypoxia -> adenosine -> A2AR pathway inhibitors may improve antitumor immunity, the recruitment of this pathway by selective drugs is expected to attenuate the autoimmune tissue damage.