title: Ectonucleotidases CD39 and CD73 on OvCA cells are potent adenosine-generating enzymes responsible for adenosine receptor 2A-dependent suppression of T cell function and NK cell cytotoxicity.
abstract: The ectonucleotidases CD39 and CD73 degrade immune stimulatory ATP to adenosine that inhibits T and NK cell responses via the A(2A) adenosine receptor (ADORA2A). This mechanism is used by regulatory T cells (T(reg)) that are associated with increased mortality in OvCA. Immunohistochemical staining of human OvCA tissue specimens revealed further aberrant expression of CD39 in 29/36 OvCA samples, whereas only 1/9 benign ovaries showed weak stromal CD39 expression. CD73 could be detected on 31/34 OvCA samples. While 8/9 benign ovaries also showed CD73 immunoreactivity, expression levels were lower than in tumour specimens. Infiltration by CD4(+) and CD8(+) T cells was enhanced in tumour specimens and significantly correlated with CD39 and CD73 levels on stromal, but not on tumour cells. In vitro, human OvCA cell lines SK-OV-3 and OaW42 as well as 11/15 ascites-derived primary OvCA cell cultures expressed both functional CD39 and CD73 leading to more efficient depletion of extracellular ATP and enhanced generation of adenosine as compared to activated T(reg). Functional assays using siRNAs against CD39 and CD73 or pharmacological inhibitors of CD39, CD73 and ADORA2A revealed that tumour-derived adenosine inhibits the proliferation of allogeneic human CD4(+) T cells in co-culture with OvCA cells as well as cytotoxic T cell priming and NK cell cytotoxicity against SK-OV3 or OAW42 cells. Thus, both the ectonucleotidases CD39 and CD73 and ADORA2A appear as possible targets for novel treatments in OvCA, which may not only affect the function of T(reg) but also relieve intrinsic immunosuppressive properties of tumour and stromal cells.
authors.affiliation: Department of Obstetrics and Gynaecology, University of Würzburg, School of Medicine, Josef-Schneider-Strasse 4, 97080 Würzburg, Germany. sebastian.haeusler@web.de
authors.forename: Sebastian F M
authors.initials: SF
authors.lastname: Häusler
authors.forename: Itsaso
authors.initials: I
authors.lastname: Montalbán del Barrio
authors.forename: Jenny
authors.initials: J
authors.lastname: Strohschein
authors.forename: P Anoop
authors.initials: PA
authors.lastname: Chandran
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Engel
authors.forename: Arnd
authors.initials: A
authors.lastname: Hönig
authors.forename: Monika
authors.initials: M
authors.lastname: Ossadnik
authors.forename: Evi
authors.initials: E
authors.lastname: Horn
authors.forename: Birgitt
authors.initials: B
authors.lastname: Fischer
authors.forename: Mathias
authors.initials: M
authors.lastname: Krockenberger
authors.forename: Stefan
authors.initials: S
authors.lastname: Heuer
authors.forename: Ahmed Adel
authors.initials: AA
authors.lastname: Seida
authors.forename: Markus
authors.initials: M
authors.lastname: Junker
authors.forename: Hermann
authors.initials: H
authors.lastname: Kneitz
authors.forename: Doris
authors.initials: D
authors.lastname: Kloor
authors.forename: Karl-Norbert
authors.initials: KN
authors.lastname: Klotz
authors.forename: Johannes
authors.initials: J
authors.lastname: Dietl
authors.forename: Jörg
authors.initials: J
authors.lastname: Wischhusen
mesh_terms: D015720:5'-Nucleotidase / Q000276:immunology / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D001081:Apyrase / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D034622:RNA Interference; D043705:Receptor, Adenosine A2A / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D043705:Receptor, Adenosine A2A; D015720:5'-Nucleotidase; C548241:NT5E protein, human; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine