Assessment of new HDAC inhibitors for immunotherapy of malignant pleural mesothelioma

Autor: Bensaid, Douae, Blondy, Thibaut, Deshayes, Sophie, Dehame, Virginie, Bertrand, Philippe, Grégoire, Marc, Errami, Mohammed, Blanquart, Christophe
Přispěvatelé: Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratory of Physiology and Physiopathology [Tetouan, BP, Morocco], Faculty of Sciences of Tetouan [Morocco], Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP), Université de Poitiers-Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Membre du Réseau Epigénétique du Cancéropôle Grand-Ouest, This work was supported by INSERM, CNRS, Région Pays de la Loire, the 'Institut de recherche en santé respiratoire des Pays de la Loire', the ‘Ligue Contre le Cancer (committees of Morbihan, Sarthe, Vendée et Loire-Atlantique), ARSMESO44, Nantes University Hospital, and INSERM (France)/ CNRST (Morocco) agreement 2015/2016., Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Bernardo, Elizabeth
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Clinical Epigenetics
Clinical Epigenetics, BioMed Central, 2018, 10 (1), ⟨10.1186/s13148-018-0517-9⟩
Clinical Epigenetics, Vol 10, Iss 1, Pp 1-11 (2018)
Clinical Epigenetics, 2018, 10 (1), ⟨10.1186/s13148-018-0517-9⟩
ISSN: 1868-7083
DOI: 10.1186/s13148-018-0517-9⟩
Popis: Background Malignant pleural mesothelioma (MPM) is a very rare and highly aggressive cancer of the pleura associated in most cases with asbestos exposure. To date, no really efficient treatments are available for this pathology. Recently, it has been shown that epigenetic drugs, particularly DNA methylation or histone acetylation modulating agents, could be very efficient in terms of cytotoxicity for several types of cancer cells. We previously showed that a hypomethylating agent (decitabine) and a histone deacetylase inhibitor (HDACi) (valproic acid (VPA)) combination was immunogenic and led to the induction of an anti-tumor immune response in a mice model of mesothelioma. However, VPA is not very specific, is active at millimolar concentrations and is responsible for side effects in clinic. To improve this approach, we studied four newly synthetized HDACi, two hydroxamates (ODH and NODH) and two benzamides (ODB and NODB), in comparison with VPA and SAHA. We evaluated their toxicity on immune cells and their immunogenicity on MPM cells in combination with decitabine. Results All the tested HDACi were toxic for immune cells at high concentrations. Combination with decitabine increased toxicity of HDACi only towards T-cell clone. A decrease in the proportion of regulatory T cells and natural killer cells was observed in particular with VPA and ODH. In MPM cells, all HDACi combinations induced NY-ESO-1 cancer testis antigen (CTA) expression and the recognition of the treated cells by a NY-ESO-1 specific T-CD8 clone. However, for MAGE-A1, MAGE-A3 and XAGE-1b mRNA expression, the results obtained depended on the HDACi used and on the CTA studied. Depending on the MPM cell line studied, molecules alone increased moderately PD-L1 expression. When combined, a higher stimulation of this immune check point inhibitor expression was observed. Decitabine-induced anti-viral response seemed to be inhibited in the presence of HDACi. Conclusions This work shows that the combination of decitabine and HDACi could be of interest for MPM immunotherapy. However, this combination induced PD-L1 expression which suggests that an association with anti-PD-L1 therapy should be performed to induce an efficient anti-tumor immune response. Electronic supplementary material The online version of this article (10.1186/s13148-018-0517-9) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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