RT Journal Article SR Electronic T1 A 5-aza-2′-deoxycytidine/valproate combination induces cytotoxic T-cell response against mesothelioma JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP 1105 OP 1116 DO 10.1183/09031936.00081310 VO 38 IS 5 A1 S. Leclercq A1 F. Gueugnon A1 B. Boutin A1 F. Guillot A1 C. Blanquart A1 A. Rogel A1 M. Padieu A1 D. Pouliquen A1 J-F. Fonteneau A1 M. Grégoire YR 2011 UL http://erj.ersjournals.com/content/38/5/1105.abstract AB Malignant pleural mesothelioma (MPM) is an aggressive tumour with a 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 tumour 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 synergised with 5-azaCdR to kill MPM cells and induce tumour antigen expression in the remaining living tumour cells. As a consequence, tumour cells expressing these antigens were recognised and lysed by specific CD8+ cytotoxic T-cells. In vivo, treatment with 5-azaCdR/VPA inhibited tumour growth, and promoted lymphocyte infiltration and an immune response against tumour 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.