title: Targeting human inducible regulatory T cells (Tr1) in patients with cancer: blocking of adenosine-prostaglandin E₂ cooperation.
abstract: BACKGROUND
  Emerging data suggest that human inducible regulatory T cells (Tr1) produce adenosine and prostaglandin E(2) and that these factors cooperate in mediating immune suppression.
  
  
  METHODS
  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 (EP(2)R) 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(+)CD39(+) and CD4(+)COX-2(+) Treg subsets increase in advanced disease and also following oncologic therapies.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pathology, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213, USA. whitesidetl@upmc.edu
authors.forename: Magis
authors.initials: M
authors.lastname: Mandapathil
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
mesh_terms: D000241:Adenosine / Q000037:antagonists & inhibitors / Q000276:immunology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000276:immunology*; D006801:Humans; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000241:Adenosine; D015232:Dinoprostone