Natural immunity enhances the activity of a DR5 agonistic antibody and carboplatin in the treatment of ovarian cancer.
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. (c)2010 AACR.
El-Gazzar
Ahmed
A
Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
Perco
Paul
P
Eckelhart
Eva
E
Anees
Mariam
M
Sexl
Veronika
V
Mayer
Bernd
B
Liu
Yanxin
Y
Mikulits
Wolfgang
W
Horvat
Reinhard
R
Pangerl
Thomas
T
Zheng
Dexian
D
Krainer
Michael
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D016190:Carboplatin / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007109:Immunity / Q000276:immunology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists*; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D016190:Carboplatin