L’inhibition HDAC induite par le valproate améliore la cytotoxicité directe des monocytes contre les cellules de mésothéliome pleural malin

Malignant pleural mesothelioma (MPM) is a rare cancer affecting mesothelial cells in the pleura. MPM is incurable and treatments only prolong patient’s survival by a few months. Monocytes are innate immunity cells that constitute the first line of defence against tumor cells. In MPM, monocytes exert immunosuppressive functions through the tumor-associated macrophages (TAMs) and the monocyte myeloid-derived suppressor cells (M-MDSCs). Their presence is associated to a bad prognosis in MPM patients. Despite their immunosuppressive functions, monocytes are also able to exert antitumor functions through phagocytosis, antibody-dependent cell-mediated cytotoxicity, cytokine and reactive substance production. The objectives of the thesis consist, on one side, to study the cytotoxic activity of monocytes against MPM cells and, on the other side, to modulate this activity by means of epigenetic regulators. Results show that monocytes exert a cytotoxic activity against MPM cells. In addition, monocyte treatment with VPA, a histone deacetylase inhibitor, significantly increases monocyte migration, their aggregation to tumor cells and their cytotoxicity against MPM cells. Finally, the molecular mechanisms of VPA involve a downregulation of the membrane receptors associated with the M2 phenotype, including CD163, CD206 and CD209. Monocyte treatment with VPA may thus be explored as a novel approach to improve MPM therapy.