Anti-CD39 and anti-CD73 antibodies A1 and 7G2 improve targeted therapy in ovarian cancer by blocking adenosine-dependent immune evasion.
The ectonucleotidases CD39 and CD73 degrade ATP to adenosine which inhibits immune responses via the A2A adenosine receptor (ADORA2A) on T and NK cells. The current study investigates the potential therapeutic use of the specific anti CD39- and anti CD73-antibodies A1 (CD39) and 7G2 (CD73) as these two ectonucleotidases are overexpressed in ovarian cancer (OvCA). As expected, NK cell cytotoxicity against the human ovarian cancer cell lines OAW-42 or SK-OV-3 was significantly increased in the presence of A1 or 7G2 antibody. While this might partly be due to antibody-dependent cell-mediated cytotoxicity, a luciferase-dependent assay for quantifying biologically active adenosine further showed that A1 and 7G2 can inhibit CD39 and CD73-dependent adenosine-generation. In turn, the reduction in adenosine levels achieved by addition of A1 and 7G2 to OAW-42 or SK-OV-3 cells was found to de-inhibit the proliferation of CD4(+) T cells in coculture with OvCA cells. Likewise, blocking of CD39 and CD73 on OvCA cells via A1 and 7G2 led to an increased cytotoxicity of alloreactive primed T cells. Thus, antibodies like A1 and 7G2 could improve targeted therapy in ovarian cancer not only by specifically labeling overexpressed antigens but also by blocking adenosine-dependent immune evasion in this immunogenic malignancy.
Department of Obstetrics and Gynecology, School of Medicine, University of Würzburg Josef-Schneider-Strasse 4, Germany ; Interdisciplinary Center for Clinical Research, School of Medicine, University of Würzburg Josef-Schneider-Strasse 4, Germany.
Sebastian Fm
SF
Häusler
Department of Obstetrics and Gynecology, School of Medicine, University of Würzburg Josef-Schneider-Strasse 4, Germany ; Interdisciplinary Center for Clinical Research, School of Medicine, University of Würzburg Josef-Schneider-Strasse 4, Germany.
Itsaso Montalbán
IM
Del Barrio
Department of Obstetrics and Gynecology, School of Medicine, University of Würzburg Josef-Schneider-Strasse 4, Germany.
Joachim
J
Diessner
Department of Obstetrics and Gynecology, School of Medicine, University of Würzburg Josef-Schneider-Strasse 4, Germany ; Else-Kröner Research Programm for Interdisciplinary Translational Immunology, School of Medicine, University of Würzburg Josef-Schneider-Strasse 4, Germany.
Roland G
RG
Stein
Department of Obstetrics and Gynecology, School of Medicine, University of Würzburg Josef-Schneider-Strasse 4, Germany.
Jenny
J
Strohschein
Department of Obstetrics and Gynecology, School of Medicine, University of Würzburg Josef-Schneider-Strasse 4, Germany.
Arnd
A
Hönig
Department of Obstetrics and Gynecology, School of Medicine, University of Würzburg Josef-Schneider-Strasse 4, Germany.
Johannes
J
Dietl
Department of Obstetrics and Gynecology, School of Medicine, University of Würzburg Josef-Schneider-Strasse 4, Germany ; Interdisciplinary Center for Clinical Research, School of Medicine, University of Würzburg Josef-Schneider-Strasse 4, Germany.
Jörg
J
Wischhusen
CD39; CD73; Ovarian cancer; adenosine; immune escape