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Clin Epigenetics. 2018 Jun 18;10:79. doi: 10.1186/s13148-018-0517-9. eCollection 2018.

Assessment of new HDAC inhibitors for immunotherapy of malignant pleural mesothelioma.

Author information

1
CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France.
2
Laboratory of Physiology and Physiopathology, Faculty of Sciences of Tetouan, Avenue de Sebta Mhannech II, 93002, Tetouan, BP, Morocco.
3
Institut de Chimie des Milieux et Matériaux de Poitiers, UMR CNRS 7285, 4 rue Michel Brunet, TSA 521106, B27, 86073, Poitiers, France.
4
Réseau épigénétique du Cancéropôle Grand Ouest, Nantes, France.
5
CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France. christophe.blanquart@inserm.fr.
6
Réseau épigénétique du Cancéropôle Grand Ouest, Nantes, France. christophe.blanquart@inserm.fr.
7
CRCINA, IRS-UN, 8 Quai Moncousu, BP70721, 44007, Nantes Cedex 1, France. christophe.blanquart@inserm.fr.

Abstract

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.

KEYWORDS:

CD8+ T-cell clone; Decitabine (5-aza-2′-deoxycytidine); Epigenetic drugs; HDAC inhibitors; Immunotherapy; Malignant pleural mesothelioma; PD-L1; Tumor antigen

Conflict of interest statement

Mesothelioma cell line use in this work belongs to a bio-collection of mesothelioma samples from patients (DC-2011-1399) recognized by the French ministry of research. All recruited patients had received no prior anticancer therapy and gave signed, informed consent.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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