title: A 5-aza-2'-deoxycytidine/valproate combination induces cytotoxic T-cell response against mesothelioma.
abstract: 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.
authors.affiliation: INSERM, U892, Institut de Recherche Thérapeutique, Université de Nantes, Nantes, France.
authors.forename: S
authors.initials: S
authors.lastname: Leclercq
authors.forename: F
authors.initials: F
authors.lastname: Gueugnon
authors.forename: B
authors.initials: B
authors.lastname: Boutin
authors.forename: F
authors.initials: F
authors.lastname: Guillot
authors.forename: C
authors.initials: C
authors.lastname: Blanquart
authors.forename: A
authors.initials: A
authors.lastname: Rogel
authors.forename: M
authors.initials: M
authors.lastname: Padieu
authors.forename: D
authors.initials: D
authors.lastname: Pouliquen
authors.forename: J-F
authors.initials: JF
authors.lastname: Fonteneau
authors.forename: M
authors.initials: M
authors.lastname: Grégoire
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000008:administration & dosage*; D000077209:Decitabine; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D008565:Membrane Proteins / Q000276:immunology; D008654:Mesothelioma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014635:Valproic Acid / Q000008:administration & dosage*; D000077337:Vorinostat
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D000077337:Vorinostat; D014635:Valproic Acid; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine