Adenosine Targeting as a New Strategy to Decrease Glioblastoma Aggressiveness

Abstract

Glioblastoma is the most commonly malignant and aggressive brain tumor, with a high mortality rate. The role of the purine nucleotide adenosine and its interaction with its four subtypes receptors coupled to the different G proteins, A1, A2A, A2B, and A3, and its different physiological functions in different systems and organs, depending on the active receptor subtype, has been studied for years. Recently, several works have defined extracellular adenosine as a tumoral protector because of its accumulation in the tumor microenvironment. Its presence is due to both the interaction with the A2A receptor subtype and the increase in CD39 and CD73 gene expression induced by the hypoxic state. This fact has fueled preclinical and clinical research into the development of efficacious molecules acting on the adenosine pathway and blocking its accumulation. Given the success of anti-cancer immunotherapy, the new strategy is to develop selective A2A receptor antagonists that could competitively inhibit binding to its endogenous ligand, making them reliable candidates for the therapeutic management of brain tumors. Here, we focused on the efficacy of adenosine receptor antagonists and their enhancement in anti-cancer immunotherapy.

Keywords: A2AAR antagonist; adenosine; adenosine receptors; glioblastoma; immune evasion; tumor microenvironment.

Figure 1

Figure created with Biorender.com. Classification of brain tumors (A). Main symptoms of brain tumors (B).

Figure 2

Figure created with Biorender.com. Production of adenosine starts from its precursors ATP, ADP, and AMP and subsequent binding of the nucleoside with the respective receptors A1, A2_A, A2_B, and A3.

Figure 3

Figure created with Biorender.com. Right: induction of the immune response by antigen presenting by APC, with consequent activation of effector CD8⁺ T cells and recruitment of immune cells, with the elimination of the tumor cell. Left: lack of immune response, following antigen presentation by non-professional APC cells. The tumor microenvironment, characterized by hypoxia and the presence of inhibitory cytokines and cytokines such as IL-10 and TGF-β, leads to inactivation and/or tolerance of effector T cells with the consequent escape of the tumor from the immune response.

Figure 4

The main adenosine receptor antagonists divided into xanthine derivatives and non-xanthine derivatives.