Kinetics of Host Cell Recruitment During Dissemination of Diffuse Malignant Peritoneal Mesothelioma

Diffuse malignant mesothelioma is an aggressive tumor which displays a median survival of 11.2 months and a 5-year survival of less than 5% emphasizing the need for more effective treatments. This study uses an orthotopic model of malignant mesothelioma established in syngeneic, immunocompetent C57Bl/6 mice which produce malignant ascites and solid tumors that accurately replicate the histopathology of the human disease. Host stromal and immune cell accumulation within malignant ascites and solid tumors was determined using immunofluorescent labeling with confocal microscopy and fluorescence-activated cell sorting. An expression profile of cytokines and chemokines was produced using quantitative real-time PCR arrays. Tumor spheroids and solid tumors show progressive growth and infiltration with host stromal and immune cells including macrophages, endothelial cells, CD4⁺ and CD8⁺ lymphocytes, and a novel cell type, myeloid derived suppressor cells (MDSCs). The kinetics of host cell accumulation and inflammatory mediator expression within the tumor ascites divides tumor progression into two distinct phases. The first phase is characterized by progressive macrophage and T lymphocyte recruitment, with a cytokine profile consistent with regulatory T lymphocytes differentiation and suppression of T cell function. The second phase is characterized by decreased expression of macrophage chemotactic and T-cell regulating factors, an increase in MDSCs, and increased expression of several cytokines which stimulate differentiation of MDSCs. This cellular and expression profile suggests a mechanism by which host immune cells promote diffuse malignant mesothelioma progression.