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.