DISTRIBUTION AND FUNCTION OF THE COMPLEMENT PROTEIN C1Q IN MALIGNANT PLEURAL MESOTHELIOMA MICROENVIRONMENT

Introductions and Objectives. The complement component C1q has been shown to be abundantly expressed in the microenvironment of several solid tumors where it can act as a tumor-promoting factor favoring adhesion, migration, and proliferation of cancer cells as well as angiogenesis and metastasis.In this study, we dissected the non-convectional function of C1q within the microenvironment of malignant pleural mesothelioma (MPM), a highly aggressive asbestos-related neoplasm, and in particular its role in regulating of human macrophage polarization. Within the MPM environment, C1q has been shown to be able to induce M2-like polarization of macrophages. Materials and Methods. The presence of C1q was evaluated in the microenvironment of MPM human sections by semiquantitative immunohistochemical analysis. Human mesothelioma cells were also isolated from pleural biopsies, characterized by immunofluorescence, cytofluorimetric analysis and their production of cytokines was evaluated by qPCR and ELISA. Cells were used for adhesion and migration experiments. Human Mφ were incubated with MPM conditioned medium and their phenotype and production of C1q were evaluated by qPCR. Finally, by immunohistochemical analyses, the expression of the CD163 M2-like marker was evaluated. Results. C1q was variably expressed in the stromal microenvironment of different mesothelioma histotypes, showing a higher expression in the epithelioid variant. The pattern distribution of C1q was consistent with its expression in tumor-infiltrating myeloid elements, whereas mesothelioma cells proved to be consistently negative. C1q was able to induce adhesion and proliferation of neoplastic cells via enhancement of ERK1/2, SAPK/JNK, and p38 phosphorylation. Our PCR data suggested that macrophages treated with MPM conditioning medium showed an M2-like phenotypicprofile (CD206 and IL-10 upregulation) characterized by the significant upregulation of C1q production. Furthermore, immunohistochemical analyses confirmed the conspicuous expression of the M2-like marker CD163 by MPM-infiltrating macrophages. Conclusions. C1q was highly expressed in MPM and enhanced malignant cell adhesion and proliferation. Human mesothelioma cells increased the C1q production ability by macrophages. In MPM, C1q may be involved in the M2- like polarization of macrophages eventually favoring an anti-inflammatory microenvironment and promoting tumor progression. Our data identify C1q as a relevant macrophageassociated marker potentially involved in the invasion and immune escape of MPM clones and open a new prospect about interfering with non-conventional complement functions in this pathological setting.