Role of adenosine in tumor progression: focus on A2B receptor as potential therapeutic target

Abstract

Adenosine receptors are a family of G-coupled receptors which mediate the antiinflammatory and immune-suppressive effects of adenosine in a damaged tissue. A large number of evidence indicate that the accumulation of adenosine under hypoxic conditions favors tumor progression, helping cancer cells to evade immune responses. Tumor cells and/ or lymphoid and myeloid cells can express the adenosine-generating enzyme CD73 and/or A 2A receptor, which in turn strongly suppresses an effective T-cell-mediated response, while promotes the activity of suppressive cells such as Treg and myeloid-derived suppressor cells. CD73 inhibitors and A 2A antagonists, either as single agents, or in combination with immune-checkpoints inhibitors such as anti PD-1 monoclonal antibodies, are currently in Phase I clinical trial in cancer patients. Recent studies show that A 2B receptor plays an important role in mediating the pro-tumor effects of adenosine, since its selective blockade can inhibit tumor growth in some murine tumor models. Targeting A 2B receptor reduces immunosuppression induced by myeloid cells and inhibits the stromal cells activity within the tumor microenvironment, limiting tumor angiogenesis and metastatic processes. Here, the authors review the current data on involvement of A 2B receptor in regulating tumor progression and discuss the development of A 2B receptor inhibitors as potential therapeutic agents in cancer treatment. Key words:CD73/A 2 adenosine receptors axis, A 2B adenosine receptor, tumor immunity, tumor metastasis, tumor angiogenesis, cancer treatment ABSTRACTArticle history:

Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab

“…Numerous pre-clinical studies have demonstrated that adenosinergic pathway-targeted therapies can significantly reduce tumor growth and metastasis, improving the T-cell-mediated anti-tumor response [ 48 – 52 ] and synergize with antibodies anti-PD1 and anti-CTLA4 [ 53 – 56 ], establishing the bases for ongoing clinical trials [NCT02503774 and NCT02655822]. In this study, we found that the activity of sCD73 determined in the serum before treatment with nivolumab is inversely associated with objective response to nivolumab, leading us to suggest this marker as possible candidate to discriminate responders to non-responders.…”

A2B Adenosine Receptor and Cancer

“…Adenosine was demonstrated to promote VEGF production in rat myocardial myoblasts [97] and in macrophages from C57BL/6 mice [98] It has been demonstrated that AR stimulation could increase VEGF production five-fold in tumor-associated CD45 + immune cells, an effect that is not observed in CD45 + cells from A 2B AR KO mice [96] The A 2B AR induces production of VEGF [23,96,99] and interleukin (IL)-8 in human melanoma cells [46], which are essential for tumor angiogenesis. Bay60-6583, a selective A 2B AR agonist, was demonstrated to induce in tumor expression of VEGF-A [100]. A 2B AR inhibition by a selective antagonist PSB-1115 21 significantly decreased tumor growth by blocking angiogenesis and increasing T cells numbers within the tumor microenvironment.…”

“…DPP4 inhibitor vildagliptin has been reported to suppress lung cancer growth via a macrophage-mediated mechanism [110]. Considering the increased adenosine concentration and increased A 2B AR expression in the tumor microenvironment [17,31,100] together with the high expression levels of both A 2B AR and DPP4 in macrophages and dendritic cells, growing evidence suggests a critical role of A 2B AR together with CD39 and CD73 in modulating cancer progression at least in part via immune suppression. Furthermore, DPP4 physically associates with adenosine deaminase, which controls adenosine concentration and binds to the A 2B AR.…”

Adenosine, Via A 2B Receptors, Inhibits Human (P-SMC) Progenitor Smooth Muscle Cell Growth

“…From the therapeutic perspective, several adenosine receptor agonists and antagonists, as well as adenosine synthesis inhibitors, are under development for clinical use. 38,39 A 2B agonists are being developed to target cardiovascular disease 14 ; whereas, A 2B antagonists and CD73 inhibitors are being developed to target angiogenesis in cancer/tumors, 40,41 renal fibrosis, pulmonary fibrosis associated with chronic obstructive pulmonary disease, pulmonary hypertension, and dermal fibrosis. As adenosine can have both beneficial and deleterious effects, the challenge going forward is to design drugs that maximize efficacy and minimize deleterious side effects.…”