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 C 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 C 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 C cells in PE but not peripheral blood of mesothelioma patients or healthy donors. CD73 expression was inducible on CD14 C cells with sPE, cyclic-AMP (cAMP)-inducers (forskolin and prostaglandin-E 2 (PGE 2 )) and adenosine. Inhibition of PGE 2 receptors or adenosine A 2 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 C cells. TNFa production by CD73 C CD14 C cells was significantly impaired in the presence of AMP, confirming immunosuppressive function. Taken together, CD73 expression can be induced by PGE 2 , cAMP or adenosine on human CD14 C cells. We suggest that targeting this autocrine loop is a valid therapeutic approach in mesothelioma that may also enhance immunotherapy.

Dominant immunosuppression of dendritic cell function by prostate‐cancer‐derived exosomes

“…We were interested in establishing the mechanism of exosome‐induced CD73 expression on DC. As it has been shown in our laboratory recently that PGE 2 induces CD73 on primary CD14 + cells [19], we tested whether PGE 2 was contributing to the induction of CD73 on DC. DC treatment for 24 h with PGE 2 (50 nM) or CME from DU145 C and DU145 KD cultures induced CD73 expression (Figure 5(a)).…”

“…DC treatment for 24 h with PGE 2 (50 nM) or CME from DU145 C and DU145 KD cultures induced CD73 expression (Figure 5(a)). To determine if it was exosomal PGE 2 that was inducing the effect, DC were treated with PGE 2 receptor antagonists before being cultured with exosomes (Figure 5(b)) at a concentration established previously [19]. Two out of four PGE 2 prostanoid receptors, EP2 and EP4, that had been shown to be present on DC [20] were inhibited before the addition of exosomes to DC.…”

“…A CD8 + T‐cell line was developed from a HLA‐A2 + healthy donor by repeated stimulation of nonadherent PBMCs with autologous DC loaded with 2 mg/ml 5T4 [17–25] peptide (RLARLALVL; ProImmune), as described previously [18].…”

Targeting Adenosine in Cancer Immunotherapy to Enhance T-Cell Function

“…Namely, hypoxia-induced (74, 75) HIF1α (76–79) and Sp1 (80) activity promotes expression of these ecto-nucleotidases. Along the same lines, signaling pathways initiated by inflammation-associated molecules, such as IL-2 (81), IL-6 (66, 82), IL-1β (83), TNFα (83–85), type I IFNs (86, 87), IL-27 (66, 88), TGFβ (82, 89, 90) as well as by inducers of the Wnt (91, 92) or cAMP (83, 93–95) signaling pathways also boost CD39 (66, 81, 82, 88, 89, 95) and CD73 (81–87, 89–94) levels.…”

Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review)

“…However, inhibition of COX-2 using non-steroidal anti-inflammatory drugs (NSAIDs) and specific COX-2 inhibitors is associated with various side effects, including gastric ulcers and myocardial infarction (9), which have limited the use of these drugs (10). As a primary prostanoid derived from cOX-2, PGE2 can also promote the activities of tumor cells (11); therefore, inhibition of the biological activities of PGE2 at different levels may maintain the anticancer properties of cOX-2 inhibition and also help prevent side effects (12). Among four pharmacologically different G protein-coupled plasma membrane receptors of PGE2, the EP2 subunit is an important mediator of numerous physiological and pathological processes, and may be the most useful targeted receptor in anticancer treatment (13).…”