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

Abstract

Introduction: Emerging data suggest that human inducible regulatory T cells (Tr1) produce adenosine and prostaglandin E₂ and that these factors cooperate in mediating immune suppression.

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 PGE₂ signal via adenosine 2A receptor (A_2AR) and prostaglandin E₂ 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⁺CD39⁺ and CD4⁺COX-2⁺ Treg subsets increase in advanced disease and also following oncologic therapies.

Expert opinion: Pharmacologic blocking of adenosine–PGE₂ 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.

Keywords::

• adenosine
• cancer
• CD39
• CD73
• PGE₂
• Treg

Notes

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