cytotoxicity; histone deacetylase; macrophage; monocyte; pleural mesothelioma; tumor microenvironment; valproate; Oncology; Cancer Research
Abstract :
[en] The composition of the tumor microenvironment (TME) mediates the outcome of chemo- and immunotherapies in malignant pleural mesothelioma (MPM). Tumor-associated macrophages (TAMs) and monocyte myeloid-derived immunosuppressive cells (M-MDSCs) constitute a major fraction of the TME. As central cells of the innate immune system, monocytes exert well-characterized functions of phagocytosis, cytokine production, and antibody-dependent cell-mediated cytotoxicity (ADCC). The objective of this study was to evaluate the ability of monocytes to exert a direct cytotoxicity by cell-to-cell contact with MPM cells. The experimental model is based on cocultures between human blood-derived monocytes sorted by negative selection and mesothelioma cell lines. Data show (i) that blood-derived human monocytes induce tumor cell death by direct cell-to-cell contact, (ii) that VPA is a pharmacological enhancer of this cytotoxic activity, (iii) that VPA increases monocyte migration and their aggregation with MPM cells, and (iv) that the molecular mechanisms behind VPA modulation of monocytes involve a downregulation of the membrane receptors associated with the M2 phenotype, i.e., CD163, CD206, and CD209. These conclusions, thus, broaden our understanding about the molecular mechanisms involved in immunosurveillance of the tumor microenvironment and open new prospects for further improvement of still unsatisfactory MPM therapies.
Disciplines :
Oncology
Author, co-author :
Hoyos, Clotilde ✱; Université de Liège - ULiège > TERRA Research Centre
Fontaine, Alexis ✱; Université de Liège - ULiège > TERRA Research Centre
Jacques, Jean-Rock ; Université de Liège - ULiège > Département GxABT > Microbial technologies
Heinen, Vincent ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pneumologie - allergologie
Louis, Renaud ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pneumologie - allergologie
Duysinx, Bernard ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pneumologie - allergologie
Scherpereel, Arnaud; Department of Pneumology and Thoracic Oncology, CHU Lille, 59037 Lille, France
Wasielewski, Eric; Department of Pneumology and Thoracic Oncology, CHU Lille, 59037 Lille, France
Jamakhani, Majeed ✱; Université de Liège - ULiège > Département GxABT > Microbial technologies
Hamaïdia, Malik ✱; Université de Liège - ULiège > Département GxABT > Microbial technologies
Willems, Luc ✱; Université de Liège - ULiège > Département GxABT > Microbial technologies
✱ These authors have contributed equally to this work.
Language :
English
Title :
HDAC Inhibition with Valproate Improves Direct Cytotoxicity of Monocytes against Mesothelioma Tumor Cells
Funding: This research was funded by the Fonds National de la Recherche Scientifique (FNRS), the Télévie, the Belgian Foundation against Cancer (FBC), the Fonds Spéciaux pour la Recherche de l’Université de Liège and the Fondation Léon Fredericq (FLF). C.H., A.F., M.J., M.H. and L.W. are
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