PURPOSE There are several agents in early clinical trials targeting components of the adenosine pathway including A2AR and CD73. The identification of cancers with a significant adenosine drive is critical to understand the potential for these molecules. However, it is challenging to measure tumor adenosine levels at scale, thus novel, clinically tractable biomarkers are needed. EXPERIMENTAL DESIGN We generated a gene expression signature for the adenosine signaling using regulatory networks derived from the literature and validated this in patients. We applied the signature to large cohorts of disease from The Cancer Genome Atlas (TCGA) and cohorts of immune checkpoint inhibitor-treated patients. RESULTS The signature captures baseline adenosine levels in vivo (r 2 = 0.92, P = 0.018), is reduced after small-molecule inhibition of A2AR in mice (r 2 = -0.62, P = 0.001) and humans (reduction in 5 of 7 patients, 70%), and is abrogated after A2AR knockout. Analysis of TCGA confirms a negative association between adenosine and overall survival (OS, HR = 0.6, P < 2.2e-16) as well as progression-free survival (PFS, HR = 0.77, P = 0.0000006). Further, adenosine signaling is associated with reduced OS (HR = 0.47, P < 2.2e-16) and PFS (HR = 0.65, P = 0.0000002) in CD8+ T-cell-infiltrated tumors. Mutation of TGFβ superfamily members is associated with enhanced adenosine signaling and worse OS (HR = 0.43, P < 2.2e-16). Finally, adenosine signaling is associated with reduced efficacy of anti-PD1 therapy in published cohorts (HR = 0.29, P = 0.00012). CONCLUSIONS These data support the adenosine pathway as a mediator of a successful antitumor immune response, demonstrate the prognostic potential of the signature for immunotherapy, and inform patient selection strategies for adenosine pathway modulators currently in development.

中文翻译：

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腺苷信号转导可预测癌症结果，并具有免疫治疗反应的预测效用。

目的在早期临床试验中，有几种药物针对腺苷途径的成分，包括A2AR和CD73。识别具有重要腺苷驱动力的癌症对于了解这些分子的潜力至关重要。然而，大规模测量肿瘤腺苷水平具有挑战性，因此需要新颖的，临床上易于治疗的生物标志物。实验设计我们使用源自文献的调节网络为腺苷信号产生了基因表达特征，并在患者中进行了验证。我们将签名应用于癌症基因组图谱（TCGA）的大型疾病队列和免疫检查点抑制剂治疗的患者队列。结果签名捕获了体内的基线腺苷水平（r 2 = 0.92，P = 0.018），在小鼠（r 2 = -0.62，P = 0.001）和人（7例患者中有5例减少，70％）中对A2AR进行小分子抑制后，其降低；在敲除A2AR后被废止。TCGA的分析证实了腺苷与总生存期（OS，HR = 0.6，P <2.2e-16）以及无进展生存期（PFS，HR = 0.77，P = 0.0000006）之间呈负相关。此外，在CD8 + T细胞浸润的肿瘤中，腺苷信号传导与OS降低（HR = 0.47，P <2.2e-16）和PFS（HR = 0.65，P = 0.0000002）相关。TGFβ超家族成员的突变与增强的腺苷信号传导和更差的OS相关（HR = 0.43，P <2.2e-16）。最后，在已发表的队列研究中，腺苷信号传导与抗PD1治疗的疗效降低相关（HR = 0.29，P = 0.00012）。