TY - JOUR T1 - 5-aza-2′-deoxycytidine/valproate combination induces CTL response against mesothelioma JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/09031936.00081310 SP - erj00813-2010 AU - S. Leclercq AU - F. Gueugnon AU - B. Boutin AU - F. Guillot AU - C. Blanquart AU - A. Rogel AU - M. Padieu AU - D. Pouliquen AU - J-F. Fonteneau AU - M. Grégoire Y1 - 2011/01/01 UR - http://erj.ersjournals.com/content/early/2011/04/20/09031936.00081310.abstract N2 - Malignant pleural mesothelioma (MPM) is an aggressive tumor with limited response to conventional therapy. The aim of this study was to evaluate the anticancer effect of a DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (5-azaCdR), and two histone deacetylase inhibitors, valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA).Human mesothelioma cells were treated with each epigenetic drug, either alone or in combinations. The cytotoxic effects on treated cells, and the expression of specific tumor antigens, were evaluated. The recognition of treated cells by a specific CD8+ T-cell clone was also measured. Additionally, the effect of combined treatments was tested in a murine model of mesothelioma.We showed that VPA and SAHA synergized with 5-azaCdR to kill MPM cells and to induce tumor antigen expression in the remaining living tumor cells. As a consequence, tumor cells expressing these antigens were recognized and lysed by specific CD8+ cytotoxic T-cells. In vivo, treatment with 5-azaCdR/VPA inhibited tumor growth and promoted lymphocyte infiltration and an immune response against tumor cells.Appropriate epigenetic drug combinations, in addition to inducing mesothelioma cell death, also affect the immunogenic status of these cells. This property could be exploited in clinical investigations to develop MPM treatments combining chemotherapeutic and immunotherapeutic approaches. ER -