Intrapleural hyperthermic chemotherapy induces pro-immunogenic e-selectin expression in the vasculature of malignant pleural mesothelioma

Abstract

Abstract Objective Malignant pleural mesothelioma (MPM) is a deadly disease with dismal prognosis. Prior studies combining surgery with intrapleural hyperthermic chemotherapy (IPHC) have shown improved survivals in selected patients with MPM. However, the mechanisms by which IPHC acts on MPM and its microenvironment remains unknown. Here we focus on tumor endothelial adhesion molecule expression patterns. Methods First, we determined the impact of IPHC on MPM tumor and vascular compartments in vitro using a novel bioincubater for hyperthermic cell culture. The cytotoxicity of normo (37 °C) / hyperthermic (42 °C for 60 minutes) cisplatin/carboplatin therapies were evaluated on four MPM (MSTO211H, H-Meso, AE17 and AB12) and one endothelial (EC-RF24) cell lines at a minimum of 24 hours using a presto-blue assay. Second, we treated endothelial cells with IPHC (60 min, 42 °C at optimized cytotoxic concentrations) and determined its impact on pro-immunogenic adhesion molecule (E-selectin, VE-cadherin, VCAM and Connexin-43) expression at 24 hours by Western blot. Results Tumor and endothelial cell viability decreased with increasing doses of both chemotherapeutics but was not affected by hyperthermia (IC50 with or without hyperthermia of each cell line at 24 hours reported in Figure 1A). Interestingly, endothelial cell line IC50 was much higher than that of MPM tumor cells for both chemotherapeutics (Figure 1A). Pro-immunogenic adhesion molecule E-Selectin was increased at 24 hours by IPHC with both chemotherapeutics while VE-Cadherin, VCAM and Connexin-43 were not affected (Figure 1B). Conclusion Hyperthermia adds no cytotoxicity to intrapleural chemotherapy. However, IPHC favors pro-immunogenic endothelial E-selectin expression. The latter could help induce patient immunity against their MPM and improve survival. Confirmation of these findings in vivo is mandatory.