Figure 7. A model for EZH2-dependent immunoediting of mesothelioma cells by autologous macrophages.

Schematic representation of direct and indirect cytotoxicities mediated by ROS and peroxynitrites produced by macrophages. Oxidative stress induces tyrosine nitration in tumor cells, leading to apoptosis and phagocytosis by macrophages. Inhibition of EZH2 reduces direct cytotoxicity exerted by macrophages without affecting ROS production but increases PD-1 expression. The engagement of PD-1 at the synapse between macrophages and mesothelioma cells impairs killing activity of macrophages. The combination of an EZH2 inhibitor (such as tazemetostat) and immune checkpoint inhibitor that targets PD-1 (e.g., pembrolizumab, nivolumab) restores immunoediting activity of macrophages.