Cancer Immunology, Immunotherapy

, 60:1405

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

  • Sebastian F. M. Häusler
  • Itsaso Montalbán del Barrio
  • Jenny Strohschein
  • P. Anoop Chandran
  • Jörg B. Engel
  • Arnd Hönig
  • Monika Ossadnik
  • Evi Horn
  • Birgitt Fischer
  • Mathias Krockenberger
  • Stefan Heuer
  • Ahmed Adel Seida
  • Markus Junker
  • Hermann Kneitz
  • Doris Kloor
  • Karl-Norbert Klotz
  • Johannes Dietl
  • Jörg Wischhusen
Original article

DOI: 10.1007/s00262-011-1040-4

Cite this article as:
Häusler, S.F.M., Montalbán del Barrio, I., Strohschein, J. et al. Cancer Immunol Immunother (2011) 60: 1405. doi:10.1007/s00262-011-1040-4

Abstract

The ectonucleotidases CD39 and CD73 degrade immune stimulatory ATP to adenosine that inhibits T and NK cell responses via the A2A adenosine receptor (ADORA2A). This mechanism is used by regulatory T cells (Treg) 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 Treg. 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 Treg but also relieve intrinsic immunosuppressive properties of tumour and stromal cells.

Keywords

Ovarian cancerImmune escapeAdenosineCD39CD73

Abbreviations

CFDA-SE

Carboxyfluorescein diacetate succinimidyl ester

ENTPD1

Ectonucleoside triphosphate diphosphohydrolase 1

FITC

Fluorescein isothiocyanate

NK

Natural killer (cells)

OvCA

Ovarian cancer

PBMC

Peripheral blood mononuclear cells

shRNA

Short hairpin RNA

siRNA

Short interfering RNA

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Sebastian F. M. Häusler
    • 1
    • 4
  • Itsaso Montalbán del Barrio
    • 1
    • 4
  • Jenny Strohschein
    • 1
  • P. Anoop Chandran
    • 1
    • 3
  • Jörg B. Engel
    • 1
  • Arnd Hönig
    • 1
  • Monika Ossadnik
    • 1
    • 4
  • Evi Horn
    • 1
  • Birgitt Fischer
    • 1
  • Mathias Krockenberger
    • 1
  • Stefan Heuer
    • 1
  • Ahmed Adel Seida
    • 1
    • 4
  • Markus Junker
    • 1
    • 4
  • Hermann Kneitz
    • 2
  • Doris Kloor
    • 5
    • 6
  • Karl-Norbert Klotz
    • 7
  • Johannes Dietl
    • 1
  • Jörg Wischhusen
    • 1
    • 4
  1. 1.Department of Obstetrics and GynaecologyUniversity of Würzburg, School of MedicineWürzburgGermany
  2. 2.Department of DermatologyUniversity of Würzburg, School of MedicineWürzburgGermany
  3. 3.Graduate School for Life SciencesUniversity of Würzburg, School of MedicineWürzburgGermany
  4. 4.Interdisciplinary Centre for Clinical ResearchUniversity of Würzburg, School of MedicineWürzburgGermany
  5. 5.Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and ToxicologyEberhard-Karls-University Hospitals and ClinicsTübingenGermany
  6. 6.Interfaculty Centre of Pharmacogenomics and Pharmaceutical Research (ICePhA)University of TübingenTübingenGermany
  7. 7.Institute of Pharmacology and ToxicologyUniversity of WürzburgWürzburgGermany