Remodeling of mice macrophages induced by trabectedin

Abstract

Immune cells have an important role in the tumor-microenvironment. Macrophages may tune the immune response toward inflammatory or tolerance pathways. Tumor associated macrophages (TAM) have immunosuppressive functions and they are considered a therapeutic target in cancer. The aim of this study was to evaluate the effects of trabectedin, a new class of antitumor agent, on the tumor-microenvironment through the study of electrophysiological and molecular phenotype of macrophages. Experiments were performed using the whole-cell patchclamp configuration of the patch-clamp technique in resident peritoneal mouse macrophages under different types of polarization. Trabectedin decreased macrophages viability and increased ROS production. Trabectedin does not directly interact with KV1.5 and KV1.3 channels, but treatment (16h) of macrophages with sub-cytotoxic concentrations (0.1-5 nM) increased their KV current in a concentration-dependent manner due to an upregulation of KV1.3 channels. In vitro generated TAM (TAMiv), by a co-culture of ID8 cells and macrophages, exhibited a M2 phenotype. TAMiv generated a small KV current, similarly to M2 polarized macrophages, and expressed high levels of M2 markers. In this study, we demonstrated that TAMiv polarization could be re-educated by using sub-cytotoxic concentration of trabectedin. TAMiv treated with sub-cytotoxic concentrations of trabectedin exhibited an upregulation of KV1.3 channels and their M2 phenotype changed towards M1 pro-inflammatory one.