Adenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironment.
Adenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironment.
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DOI：
10.1158/0008-5472.can-13-3581
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发表时间：
2014-12-15
期刊：
影响因子：
11.2
通讯作者：
Linden J
中科院分区：
文献类型：
--
作者：
Cekic C;Linden J
腺苷A2 A受体（A2 AR）阻断剂增强先天性和适应性免疫应答。然而，小鼠遗传学研究表明，A2 AR缺失并不能抑制所有肿瘤类型的生长。在目前的研究中，我们发现在肿瘤接种后两周内，Adora 2a −/−小鼠中异位黑色素瘤和膀胱肿瘤的生长率增加。宿主中的A2 AR缺失减少了CD 8 + T细胞的数量和所有T细胞的效应记忆分化。为了检查T细胞中的内在功能，我们产生了携带A2 AR的T细胞特异性缺失的小鼠。在该宿主品系中，荷瘤小鼠表现出异位黑色素瘤生长增加、肿瘤相关T细胞数量减少、效应记忆分化减少和抗原经历细胞上抗凋亡IL-7 R α（CD 127）表达减少。肿瘤内药物阻断同样降低了野生型宿主肿瘤内的CD 8 + T细胞密度。我们发现，对黑色素瘤细胞具有特异性的A2 AR熟练的CD 8 + T细胞在肿瘤中显示出相对的存活优势。因此，废除A2 AR信号传导似乎减少了肿瘤微环境中T细胞的IL-7 R表达、存活和分化。这些结果的一个含义是，由于受损的T细胞维持和效应子/记忆分化，可以在一些肿瘤微环境中克服可以由细胞毒性T细胞的活化介导的A2 AR阻断的抗肿瘤作用。因此，我们的研究结果表明，A2 AR抑制剂在癌症免疫治疗中的有效应用可能需要仔细的剂量优化，以防止肿瘤中活化诱导的T细胞死亡。
Adenosine A2A receptor (A2AR) blockade enhances innate and adaptive immune responses. However, mouse genetic studies have shown that A2AR deletion does not inhibit the growth of all tumor types. In the current study, we showed that growth rates for ectopic melanoma and bladder tumors are increased in Adora2a−/− mice within two weeks of tumor inoculation. A2AR deletion in the host reduced numbers of CD8+ T cells and effector-memory differentiation of all T cells. To examine intrinsic functions in T cells, we generated mice harboring a T cell-specific deletion of A2AR. In this host strain, tumor-bearing mice displayed increased growth of ectopic melanomas, decreased numbers of tumor-associated T cells, reduced effector-memory differentiation and reduced anti-apoptotic IL-7Rα (CD127) expression on antigen-experienced cells. Intratumoral pharmacological blockade similarly reduced CD8+ T cell density within tumors in wild-type hosts. We found that A2AR-proficient CD8+ T cells specific for melanoma cells displayed a relative survival advantage in tumors. Thus, abrogating A2AR signaling appeared to reduce IL-7R expression, survival and differentiation of T cells in the tumor microenvironment. One implication of these results is that the anti-tumor effects of A2AR blockade that can be mediated by activation of cytotoxic T cells may be overcome in some tumor microenvironments as a result of impaired T cell maintenance and effector/memory differentiation. Thus, our findings imply that the efficacious application of A2AR inhibitors for cancer immunotherapy may require careful dose optimization to prevent activation-induced T cell death in tumors.