Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.See related commentary by Sitkovsky, p. 16.This article is highlighted in the In This Issue feature, p. 1.

中文翻译：

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腺苷 2A 受体阻断剂作为治疗难治性肾细胞癌的免疫疗法。

腺苷通过触发免疫细胞上的腺苷 2A 受体 (A2AR) 介导肿瘤微环境内的免疫抑制。为了确定该途径是否可以作为免疫疗法，我们使用小分子 A2AR 拮抗剂进行了 I 期临床试验。我们发现这种分子可以在体内安全地阻断腺苷信号传导。在一个由 68 名肾细胞癌 (RCC) 患者组成的队列中，我们还观察了单独和与抗 PD-L1 抗体联合使用的临床反应，包括使用 PD-1/PD-L1 抑制剂取得进展的受试者。持久的临床益处与 CD8+ T 细胞向肿瘤的募集增加有关。治疗还可以扩大循环 T 细胞库。临床反应与预处理肿瘤活检中腺苷调节的基因表达特征相关。因此，A2AR 信号代表了一种不同于 PD-1/PD-L1 的可靶向免疫检查点，它限制了抗肿瘤免疫。意义：这项针对癌症治疗的 A2AR 拮抗剂的首次人体研究通过证明单药和抗 PD-L1 联合疗法对难治性 RCC 患者的抗肿瘤活性，确定了靶向该途径的安全性和可行性。有反应的患者在预处理肿瘤活检中具有腺苷调节的基因表达特征。参见 Sitkovsky 的相关评论，p。16.这篇文章在 In This Issue 功能中突出显示，p。1. 这项针对癌症治疗的 A2AR 拮抗剂的首次人体研究通过证明单药和抗 PD-L1 联合疗法对难治性 RCC 患者的抗肿瘤活性，确定了靶向该途径的安全性和可行性。有反应的患者在预处理肿瘤活检中具有腺苷调节的基因表达特征。参见 Sitkovsky 的相关评论，p。16.这篇文章在 In This Issue 功能中突出显示，p。1. 这项针对癌症治疗的 A2AR 拮抗剂的首次人体研究通过证明单药和抗 PD-L1 联合疗法对难治性 RCC 患者的抗肿瘤活性，确定了靶向该途径的安全性和可行性。有反应的患者在预处理肿瘤活检中具有腺苷调节的基因表达特征。参见 Sitkovsky 的相关评论，p。16.这篇文章在 In This Issue 功能中突出显示，p。1.