RESUMO
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.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Imunidade/imunologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/imunologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/agonistas , Animais , Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carboplatina/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Camundongos , Neoplasias Ovarianas/patologia , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Autoantigens have been reported in a variety of tumors, providing insight into the interplay between malignancies and the immune response, and also giving rise to novel diagnostic and therapeutic concepts. Why certain tumor-associated proteins induce an immune response remains largely elusive. RESULTS: This paper analyzes the proposed link between increased abundance of a protein in cancerous tissue and the increased potential of the protein for induction of a humoral immune response, using ovarian cancer as an example. Public domain data sources on differential gene expression and on autoantigens associated with this malignancy were extracted and compared, using bioinformatics analysis, on the levels of individual genes and proteins, transcriptional coregulation, joint functional pathways, and shared protein-protein interaction networks. Finally, a selected list of ovarian cancer-associated, differentially regulated proteins was tested experimentally for reactivity with antibodies prevalent in sera of ovarian cancer patients.Genes reported as showing differential expression in ovarian cancer exhibited only minor overlap with the public domain list of ovarian cancer autoantigens. However, experimental screening for antibodies directed against antigenic determinants from ovarian cancer-associated proteins yielded clear reactions with sera. CONCLUSION: A link between tumor protein abundance and the likelihood of induction of a humoral immune response in ovarian cancer appears evident.
