A2AR Adenosine Signaling Suppresses Natural Killer Cell Maturation in the Tumor Microenvironment
A2AR Adenosine Signaling Suppresses Natural Killer Cell Maturation in the Tumor Microenvironment
复制标题
A2AR腺苷信号传导在肿瘤微环境中抑制自然杀伤细胞的成熟
DOI：
10.1158/0008-5472.can-17-2826
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发表时间：
2018-02-15
期刊：
影响因子：
11.2
通讯作者：
Smyth, Mark J.
中科院分区：
文献类型：
--
作者：
Young, Arabella;Ngiow, Shin Foong;Smyth, Mark J.
胞外腺苷是一种关键的免疫抑制代谢物，它限制细胞毒性淋巴细胞的激活并损害抗肿瘤免疫反应。在这里，我们发现A2A腺苷受体（A2AR）的参与作为一个检查点，限制了自然杀伤（NK）细胞的成熟。A2AR的全局性和NK细胞特异性条件缺失都增加了稳态、重构和肿瘤微环境中终末成熟NK细胞的比例。值得注意的是，缺乏a2ar的终末成熟NK细胞保留了增殖能力，并在竞争性转移试验中表现出更高的重构。此外，特异性靶向NK细胞的A2AR也改善了肿瘤的控制和延迟肿瘤的发生。综上所述，我们的研究结果确定了a2ar介导的腺苷信号是nk细胞成熟和抗肿瘤免疫反应的内在负调节因子。基于这些发现，我们建议在使用A2AR拮抗剂的同时使用NK细胞为基础的治疗可以通过增强NK细胞介导的抗肿瘤免疫来提高治疗效果。意义：发现消融腺苷信号通路可促进自然杀伤细胞成熟和抗肿瘤免疫，降低肿瘤生长。(c) 2017 aacr。
Extracellular adenosine is a key immunosuppressive metabolite that restricts activation of cytotoxic lymphocytes and impairs antitumor immune responses. Here, we show that engagement of A2A adenosine receptor (A2AR) acts as a checkpoint that limits the maturation of natural killer (NK) cells. Both global and NK-cell-specific conditional deletion of A2AR enhanced proportions of terminally mature NK cells at homeostasis, following reconstitution, and in the tumor microenvironment. Notably, A2AR-deficient, terminally mature NK cells retained proliferative capacity and exhibited heightened reconstitution in competitive transfer assays. Moreover, targeting A2AR specifically on NK cells also improved tumor control and delayed tumor initiation. Taken together, our results establish A2AR-mediated adenosine signaling as an intrinsic negative regulator of NK-cell maturation and antitumor immune responses. On the basis of these findings, we propose that administering A2AR antagonists concurrently with NK cell-based therapies may heighten therapeutic benefits by augmenting NK cell-mediated antitumor immunity.Significance: Ablating adenosine signaling is found to promote natural killer cell maturation and antitumor immunity and reduce tumor growth. (C) 2017 AACR.