title: Prostaglandin E2-mediated adenosinergic effects on CD14+cells: Self-amplifying immunosuppression in cancer.
abstract: CD39 and CD73 are surface-expressed ectonucleotidases that hydrolyze ATP in a highly regulated, serial manner into ADP, AMP and adenosine. The end product, adenosine, has both tumor-promoting and immunosuppressive effects. The aim of this study was to determine CD73 expression on immune cells in pleural effusion (PE) in order to have a better understanding of the immune environment in mesothelioma. PE- or blood-derived CD14+cells of mesothelioma patients and healthy donors were analyzed by flow cytometry for the expression of CD39 and CD73. CD73-induction was studied by exposure of CD14+cells to the soluble fraction of PE (sPE), while the signaling mechanism, responsible for CD73 induction, by phosphoflow cytometry and receptor-inhibition studies. We observed CD73 expression on CD14+cells in PE but not peripheral blood of mesothelioma patients or healthy donors. CD73 expression was inducible on CD14+cells with sPE, cyclic-AMP (cAMP)-inducers (forskolin and prostaglandin-E2(PGE2)) and adenosine. Inhibition of PGE2receptors or adenosine A2receptors blocked CD73-induction by sPE. sPE treatment triggered protein kinase A and p38 activation. However, signal-transducer and activator of transcription 3 (STAT3)-blocking led to enhanced CD73 expression, demonstrating a hitherto unknown negative control of purinergic signaling by STAT3 in CD14+cells. TNFα production by CD73+CD14+cells was significantly impaired in the presence of AMP, confirming immunosuppressive function. Taken together, CD73 expression can be induced by PGE2, cAMP or adenosine on human CD14+cells. We suggest that targeting this autocrine loop is a valid therapeutic approach in mesothelioma that may also enhance immunotherapy.
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University , Cardiff, UK.
authors.forename: Saly
authors.initials: S
authors.lastname: Al-Taei
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University , Cardiff, UK.
authors.forename: Josephine
authors.initials: J
authors.lastname: Salimu
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University , Cardiff, UK.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Spary
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University , Cardiff, UK.
authors.forename: Aled
authors.initials: A
authors.lastname: Clayton
authors.affiliation: Velindre NHS Trust, Velindre Cancer Centre , Cardiff, UK.
authors.forename: Jason F
authors.initials: JF
authors.lastname: Lester
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University , Cardiff, UK.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Tabi
keywords: Adenosine; CD73; STAT3; cAMP; monocytes; pleural effusion (PE); prostaglandin-E2 (PGE2)