The programmed death (PD)‐1/PD‐ligand (PD‐L) pathway and regulatory T cells (Tregs) are essential for the maintenance of immune tolerance. Their activation in the tumour microenvironment contributes to the evasion of the transformed cells from the immune surveillance and the suppression of an antitumour immune response. Therefore, PD‐1/PD‐L1 and Tregs are important targets for cancer immunotherapy. Our review focuses on the current role of the PD‐1/PD‐L1 axis in Treg development and function in the tumour microenvironment. We also discuss combination therapy with PD‐1/PD‐L1 inhibitors and Treg‐modulating agents affecting the adenosinergic pathway, TGF‐β signalling, immune checkpoints and other approaches to downregulation of Tregs.
The immunosuppressive effect of adenosine in the microenvironment of a tumor is well established. Presently, researchers are developing approaches in immune therapy that target inhibition of adenosine or its signaling such as CD39 or CD73 inhibiting antibodies or adenosine A2A receptor antagonists. However, numerous enzymatic pathways that control ATP-adenosine balance, as well as understudied intracellular adenosine regulation, can prevent successful immunotherapy. This review contains the latest data on two adenosine-lowering enzymes: adenosine kinase (ADK) and adenosine deaminase (ADA). ADK deletes adenosine by its phosphorylation into 5′-adenosine monophosphate. Recent studies have revealed an association between a long nuclear ADK isoform and an increase in global DNA methylation, which explains epigenetic receptor-independent role of adenosine. ADA regulates the level of adenosine by converting it to inosine. The changes in the activity of ADA are detected in patients with various cancer types. The article focuses on the biological significance of these enzymes and their roles in the development of cancer. Perspectives of future studies on these enzymes in therapy for cancer are discussed.
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