Targeting human inducible regulatory T cells (Tr1) in patients with cancer: blocking of adenosine-prostaglandin E2 cooperation

Areas covered: Human Tr1 present in human tumors or blood of cancer patients express ectonucleotidases, CD39 and/or CD73, hydrolyze ATP to adenosine and are COX-2 positive. Expression of CD39 and/or CD73 on human tumors favors expansion and suppressor functions of Tr1. Adenosine and PGE(2) signal via adenosine 2A receptor (A(2A)R) and prostaglandin E-2 receptor 2 (EP2R) expressed on effector T (Teff) cells, suppressing their anti-tumor functions by a common mechanism involving upregulation of cytosolic cAMP levels and protein kinase A (PKA) type I activation. The frequency and activity of circulating CD4<SU++</SUCD39<SU++</SU and CD4<SU++</SUCOX-2<SU++</SU Treg subsets increase in advanced disease and also following oncologic therapies. Expert opinion: Pharmacologic blocking of adenosine--PGE(2) collaboration provides a clinically-feasible strategy for disarming of Treg. Used in conjunction with conventional anti-cancer drugs or immune interventions, pharmacologic inhibitors could improve outcome of oncologic therapies.