title: Vaccination with epigenetically treated mesothelioma cells induces immunisation and blocks tumour growth.
abstract: Malignant mesothelioma (MM) is an aggressive tumour associated with poor outcome in patients. Current treatments for MM are of limited efficacy. Our recent findings suggest that epigenetic drugs may induce both cytotoxicity and an immune response against MM cells. Thus, we used a mouse model of MM (AK7) to analyse how epigenetic drugs could modulate MM development in vivo. The treatment of tumour-bearing mice with an epigenetic drug already tested in clinical MM treatments (SAHA/Vorinostat) reduced the tumour mass and induced a moderate lymphocytic infiltration. However, the treatment did not stop tumour development. In order to show the potential effect of this epigenetic drug on tumour immunogenicity, in addition to cell cytotoxicity, we immunised mice either with AK7 cells pre-treated with SAHA, or with one of two cytotoxic drugs (curcumin or selenite), prior to transplantation of live AK7 cells. A specific immune response was observed only in mice immunised with AK7 cells pre-treated with the epigenetic drug (SAHA) and the tumour growth was arrested. An increase in the proportion of CD3+ CD8+ lymphocytes occurred in the peritoneal cavity. We also observed large conglomerates of immune cells in the omentum with clusters of CD8+ T cells, together with lymphocytes directed against residual AK7 cells in the interlobular connective tissue of the pancreas. Our data demonstrate that epigenetic drugs, such as SAHA, can stimulate tumour immunogenicity and improve the recognition of aggressive MM cells by the immune system in vivo.
authors.affiliation: Inserm, U892, Centre de Recherche en Cancérologie Nantes-Angers, Institut de Recherche Thérapeutique, Nantes, France.
authors.forename: Flora
authors.initials: F
authors.lastname: Guillot
authors.forename: Benoît
authors.initials: B
authors.lastname: Boutin
authors.forename: Christophe
authors.initials: C
authors.lastname: Blanquart
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Fonteneau
authors.forename: Myriam
authors.initials: M
authors.lastname: Robard
authors.forename: Marc
authors.initials: M
authors.lastname: Grégoire
authors.forename: Daniel
authors.initials: D
authors.lastname: Pouliquen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017252:CD3 Complex / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D008654:Mesothelioma / Q000276:immunology* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D012376:Rodent Diseases / Q000276:immunology / Q000517:prevention & control; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology; D014611:Vaccination / Q000379:methods*; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D017252:CD3 Complex; D016827:CD8 Antigens; D019496:Cancer Vaccines; D006877:Hydroxamic Acids; D000077337:Vorinostat