Abstract 493: The landscape of adenosine signaling in cancer

Abstract

Abstract Adenosine is a key suppressor of immune cell function. CD73 and other nucleotidases/phosphatases dephosphorylate and convert extracellular AMP into adenosine, which binds the A2A adenosine receptor (A2aR). 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 therefore critical to our understanding of the potential for these molecules. However, it is challenging to measure tumour adenosine levels on a pan-cancer scale. Here we describe the generation & validation of a gene expression signature that we use to characterise the pan-cancer landscape of adenosine signalling and its role within the tumour microenvironment. Natural Language Processing (NLP) was used to define a network of regulatory interactions between the A2aR receptor and downstream entities. 14 genes were identified as being positively regulated by A2aR and robustly expressed in tumours and so constitute the signature, which we demonstrate accurately recapitulates adenosine drive in mouse syngeneic models. We therefore applied the signature to a pan-cancer analysis of tumour transcriptomes from TCGA and found a significant negative impact on both overall survival (HR = 0.6, Cox PH p=0) and progression free survival (HR = 0.77, Cox PH p=0.0000006) in adenosine high tumours. An adenosine related survival deficit was also seen in CD8+ T-cell infiltrated tumours (OS HR = 0.47, Cox PH p=0; PFS HR = 0.65, Cox PH p=0.0000002). Studying adenosine signalling in the context of tumour genetics identified highly significant associations with TGFB super-family members including TGFBR2 (p=0.0000000013). These data support the adenosine pathway as a key mediator of a successful anti-tumour immune response, demonstrate the prognostic potential of the gene expression signature and could inform patient selection strategies for adenosine pathway modulators. Citation Format: Ben Sidders, Pei Zhang, Kelly Goodwin, Greg O'Connor, Alexandra Borodovsky, Jonathan Dry, Richard Woessner, Kris Sachsenmeier. The landscape of adenosine signaling in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 493.