Prostaglandin E2-mediated adenosinergic effects on CD14(+) cells: Self-amplifying immunosuppression in cancer.

Related Articles

Prostaglandin E2-mediated adenosinergic effects on CD14(+) cells: Self-amplifying immunosuppression in cancer.

Oncoimmunology. 2017;6(2):e1268308

Authors: Al-Taei S, Salimu J, Spary LK, Clayton A, Lester JF, Tabi Z

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 PGE2 receptors or adenosine A2 receptors 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.

PMID: 28344879 [PubMed - in process]

http://ift.tt/2ocNH4B