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Prostaglandin E2-mediated adenosinergic effects on CD14+ cells: self-amplifying immunosuppression in cancer

Al-Taei, Saly, Salimu, Josephine, Spary, Lisa Kate, Clayton, Aled ORCID:, Lester, Jason F. and Tabi, Zsuzsanna 2016. Prostaglandin E2-mediated adenosinergic effects on CD14+ cells: self-amplifying immunosuppression in cancer. OncoImmunology 6 (2) , pp. 312-318. 10.1080/2162402X.2016.1268308

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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

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: Adenosine, cAMP, CD73, monocytes, pleural effusion (PE), prostaglandin-E2 (PGE2), STAT3
Publisher: Taylor & Francis
ISSN: 2162-402X
Funders: June Hancock Mesothelioma Research Fund
Date of First Compliant Deposit: 13 January 2017
Date of Acceptance: 29 November 2016
Last Modified: 18 Feb 2024 16:44

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