L’INHIBITION DE LA MÉTHYLTRANSFÉRASE EZH2 DU COMPLEXE RÉPRESSEUR POLYCOMB FAVORISE LA RÉPONSE ANTI-TUMORALE DES MACROPHAGES M2 DIRIGÉE CONTRE LES CELLULES DU MÉSOTHÉLIOME PLEURAL MALIN

Context: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm affecting mesothelial cells from the pleura, pericardium and peritoneum. The disease is closely associated to asbestos exposure. Despite of rules to reduce workplace exposure to asbestos, incidence of mesothelioma is predicted to increase until 2020. Since MPM is resistant to conventional cancer therapies such as surgery, irradiation and chemotherapy, development of new options is urgently needed. In my project, I investigate the ability of immunotherapy to improve patients' outcome. My hypothesis postulates that tumor cells are tightly controlled by the immune system. In fact, clinical evidence indicates that tumor infiltration by tumor associated macrophages (TAMs) correlates with poor prognosis in malignant mesothelioma (MM). By attenuating the immune response, TAMs indeed promote survival of MM cells. TAMs share properties with alternative macrophages (M2) and are activated by anti-inflammatory (e.g. IL-10) or Th2-associated (i.e. IL-4, IL-13) cytokines. In contrast, classical (M1) macrophages are stimulated by interferon (IFN)-γ and microbial components (e.g. LPS).
Aim: We hypothesized that macrophage activation is mediated by a transcriptional program tightly regulated by epigenetic modifications. We focused on the Polycomb Repressive Complex 2 (PRC2) EZH2 lysine methyltransferase responsible for trimethylation of histone H3 at lysine 27 (H3K27me3).
Results: Our data show that inhibition of EZH2 reduces phagocytic activity by M2-polarised macrophages. Moreover, the cytotoxicity of supernatants conditioned by M2-macrophages is increased in presence of the EZH2 inhibitor. Finally, inhibition of EZH2 enhances the tumoricidal potential of M2 macrophages towards MM cells. We further demonstrate that macrophage killing activity requires superoxide radicals (O2.-) and peroxynitrites (ONOO-) derivatives produced by the NADPH oxidase system.
Conclusion: EzH2 inhibition implements the tumoricidal potential of macrophages and may therefore improve the efficacy of immunotherapy of MM patients.