Titel
Natural Immunity Enhances the Activity of a DR5 Agonistic Antibody and Carboplatin in the Treatment of Ovarian Cancer
Autor*in
Ahmed El-Gazzar
Medizinische Universität Wien
Autor*in
Dexian Zheng
Chinese Academy of Medical Sciences
Autor*in
Paul Perco
Emergentec Biodevelopment GmbH
... show all
Abstract
The tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) induces apoptosis specifically in cancer cells with little effect on normal cells. We have previously shown that TRAIL signaling is altered in most ovarian cancer patients and that resistance to TRAIL contributes to ovarian cancer progression. In this study, we investigated whether resistance to TRAIL may be overcome by a monoclonal TRAILR2 (DR5) agonistic antibody (AD5-10). We found that the joint presence of AD5-10 with TRAIL and natural killer (NK) cells expressing TRAIL resensitizes ovarian cancer cells to apoptosis in vitro and in vivo, respectively. The combination of AD5-10 with carboplatin exerts a more than additive effect in vitro, which may at least partially be explained by the fact that carboplatin triggers DR5 expression on ovarian cancer cells. Moreover, AD5-10 restores the sensitivity of platin-resistant ovarian cancer to carboplatin in vivo. In addition, we found that TRAIL expression and NK cells are abundant in the tumor microenvironment and that depletion of NK cells abolishes the antitumor activity of AD5-10. This indicates that NK-mediated immunosurveillance against ovarian cancer might be mediated by TRAIL and that apoptosis induced by AD5-10 requires the presence of NK cells. In conclusion, this study indicates a key role and strong antitumorigenic effect of DR5 and highlights a novel link between NK-mediated immunosurveillance and activation of DR5-mediated apoptosis in ovarian cancer. Mol Cancer Ther; 9(4); 1007–18.
Stichwort
APOPTOSIS-INDUCING LIGANDCELL-LINESTUMORICIDAL ACTIVITYMONOCLONAL-ANTIBODYANTITUMOR-ACTIVITYTRAILDEATHSURVEILLANCERECEPTORP53
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
https://phaidra.univie.ac.at/o:243645
Erschienen in
Titel
Molecular Cancer Therapeutics
Band
9
Ausgabe
4
Seitenanfang
1007
Seitenende
1018
Erscheinungsdatum
01.07.2010
Universität Wien | Universitätsring 1 | 1010 Wien | T +43-1-4277-0