Adenosine A2A receptor antagonists: blockade of adenosinergic effects and T regulatory cells

Abstract

The intensity and duration of host responses are determined by protective mechanisms that control tissue injury by dampening down inflammation. Adenosine generation and consequent effects, mediated via A2A adenosine receptors (A2AR) on effector cells, play a critical role in the pathophysiological modulation of these responses in vivo. Adenosine is both released by hypoxic cells/tissues and is also generated from extracellular nucleotides by ecto-enzymes e.g. CD39 (ENTPD1) and CD73 that are expressed by the vasculature and immune cells, in particular by T regulatory cell. In general, these adenosinergic mechanisms minimize the extent of collateral damage to host tissues during the course of inflammatory reactions. However, induction of suppressive pathways might also cause escape of pathogens and permit dissemination. In addition, adenosinergic responses may inhibit immune responses while enhancing vascular angiogenic responses to malignant cells that promote tumor growth. Novel drugs that block A2AR-adenosinergic effects and/or adenosine generation have the potential to boost pathogen destruction and to selectively destroy malignant tissues. In the latter instance, future treatment modalities might include novel 'anti-adenosinergic' approaches that augment immune clearance of malignant cells and block permissive angiogenesis. This review addresses several possible pharmacological modalities to block adenosinergic pathways and speculates on their future application together with impacts on human disease.

Figure 1

A2A adenosine receptor antagonist is expected to prevent inhibition of T cells by extracellular adenosine in inflamed or cancerous tissues. (a) The tumour tissue-produced extracellular adenosine inhibits incoming and TCR-activated antitumour T cells through activation of the cAMP-elevating A2A subtype of A2 adenosine receptors in the inflammatory or tumour microenvironment. The production of extracellular AMP adenosine is mediated by CD39 ectoenzyme, while the extracellular adenosine generation from extracellular AMP is mediated by CD73 ectoenzyme. (b) The T cells can be also inhibited by extracellular adenosine catalysed by CD39 and CD73 ectoenzymes expressed on the Treg. Treatment with A2A receptor antagonist may release antitumour T cells from inhibition in TME and facilitate the antitumour T-cell response. TCR, T-cell receptor.