Pleural Effusions from Patients with Mesothelioma Induce Recruitment of Monocytes and Their Differentiation into M2 Macrophages

Abstract

Introduction: Mesothelioma is a rare and aggressive cancer related to asbestos exposure. We recently showed that pleural effusions (PEs) from patients with mesothelioma contain high levels of the C-C motif chemokine ligand 2 (CCL2) inflammatory chemokine. In the present work, we studied the effect of CCL2 contained in mesothelioma samples, particularly on monocyte recruitment. Then, we studied the fate of these monocytes in malignant pleural mesothelioma (MPM) PEs and their impact on tumor cells' properties.

Methods: The implication of CCL2 in monocyte recruitment was evaluated using transmigration assays and a CCL2 blocking antibody. The phenotype of macrophages was determined by flow cytometry and enzyme-linked immunosorbent assay. Immunohistochemical analysis was used to support the results. Cocultures of macrophages with mesothelioma cells were performed to study cancer cell proliferation and resistance to treatment.

Results: We showed that CCL2 is a major factor of monocyte recruitment induced by MPM samples. Macrophages obtained in MPM samples were M2 macrophages (high CD14, high CD163, and interleukin-10 secretion after activation). The colony-stimulating factor 1 receptor/macrophage colony-stimulating factor (M-CSF) pathway is implicated in M2 polarization, and high levels of M-CSF were measured in MPM samples compared with benign PE (4.17 ± 2.75 ng/mL and 1.94 ± 1.47 ng/mL, respectively). Immunohistochemical analysis confirmed the presence of M2 macrophages in pleural and peritoneal mesothelioma. Finally, we showed that M2 macrophages increased mesothelioma cell proliferation and resistance to treatment.

Conclusions: These results demonstrate the implication of CCL2 in MPM pathogenesis and designate M-CSF as a new potential biomarker of MPM. This study also identifies CCL2 and colony-stimulating factor 1 receptor/M-CSF as interesting new targets to modulate pro-tumorigenic properties of the tumor microenvironment.

Keywords: CCL2; M-CSF; Macrophages; Mesothelioma; Pleural effusions.