Targeting regulatory T cells in anti-PD-1/PD-L1 cancer immunotherapy.

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-ß signalling, immune checkpoints and other approaches to downregulation of Tregs.

Adenosine-Metabolizing Enzymes, Adenosine Kinase and Adenosine Deaminase, in Cancer.

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.

Targeting adenosine and regulatory T cells in cancer immunotherapy.

Immunosuppressive activity of regulatory T cells (Tregs) is one of the mechanisms promoting carcinogenesis. Intratumoral Tregs have some phenotypic and functional traits that lower the efficiency of antitumor immune response, which makes them a good target for immunotherapy. Several approaches to cancer immunotherapy are being developed along this vector: deletion of tumor-infiltrating Tregs, inhibition of their homing to the tumor microenvironment, and functional downregulation of Tregs. Studies of the past decade have demonstrated the role of Tregs and ectonucleotidases CD39 and CD73 in the generation of immunosuppressive extracellular adenosine. Pharmacological targeting of CD39 and CD73 can restrain the activity of suppressor cells and promote the efficiency of cancer therapy. Here we review the latest data on issues regarding the role of extracellular adenosine and its receptors in antitumor immune response, adenosine generation mechanisms involving Tregs and the membrane proteins CD39 and CD73. Innovative approaches to antitumor immunotherapy and clinical studies of Treg targeting and application of anti-CD39/CD73 antibodies, adenosine receptor antagonists, and small-molecule inhibitors of ectonucleotidase activity are explored.