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
| Autor: | Ahmed Adel Seida, Stefan Heuer, Jenny Strohschein, Itsaso Montalbán del Barrio, Markus Junker, Jörg Wischhusen, Birgitt Fischer, Hermann Kneitz, Monika Ossadnik, Doris Kloor, Sebastian Häusler, Jörg B. Engel, Arnd Honig, Karl-Norbert Klotz, Mathias Krockenberger, Evi Horn, P. Anoop Chandran, Johannes Dietl |
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| Rok vydání: | 2010 |
| Předmět: |
Cytotoxicity
Immunologic Cancer Research Stromal cell Adenosine endocrine system diseases Receptor Adenosine A2A T cell T-Lymphocytes Immunology Priming (immunology) Cell Separation Biology GPI-Linked Proteins Antigens CD Cell Line Tumor medicine Immunology and Allergy Cytotoxic T cell Humans 5'-Nucleotidase Ovarian Neoplasms Apyrase Flow Cytometry Adenosine receptor Molecular biology Immunohistochemistry Killer Cells Natural medicine.anatomical_structure Oncology Cell culture Female RNA Interference CD8 medicine.drug |
| Zdroj: | Cancer immunology, immunotherapy : CII. 60(10) |
| ISSN: | 1432-0851 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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