Abstract 3844: Targeting macrophages as a novel therapeutic approach for malignant pleural mesothelioma

Abstract

Abstract Mesothelioma is a life-threatening tumor, induced by inhalation of asbestos fibers that is largely resistant to most chemotherapeutic drugs. Using a combination of immunohistochemistry and flow cytometry, we have evaluated both the presence and composition of leukocytes residing in human mesotheliomas, and have found that 1) epithelioid and mixed mesothelioma tumor subtypes contain higher percentages of CD45+ leukocytes than sarcomatous tumors, and 2) macrophages represent the most abundant immune cell subtype in mesothelioms, regardless of type (31 ± 4.6% of total CD45+). Indeed, the percentage of macrophages in mesotheliomas exceeded that found in other thoracic malignancies thus far evaluated (NSCLC cancer, 9%; esophageal, 4%). In view of recent data indicating that macrophages potentiate cancer development in some settings, and that macrophages can be targeted therapeutically to minimize some aspects of tumor progression, we investigated whether macrophages could be targeted to alter the chemosensitivity of human mesotheliomas. To address this question, we adapted a 3-dimensional (3D) spheroid growth model, enabling heterotypic culture of mesotheliomal cells and macrophages. Our data indicate that mesothelioma chemoresistance can be lowered by co-incubation with macrophages. However, the magnitude of the altered response is dependent upon macrophage phenotype. Macrophage phenotype and bioactivity is modulated by TH1 and TH2 cytokine exposure that in turn regulate either an M1 (IFN-γ & LPS) or M2 (IL-4) phenotype. M1-polarized macrophages increased the response of malignant mesothelioma spheroids to pro-apoptotic chemotherapeutic agents, including gemcitabine. Furthermore, our preliminary data indicate that primary human tumor-associated macrophages, isolated from untreated malignant mesotheliomas, exhibit similar pro-apoptotic effects when polarized with M1 cytokines, indicating that cytokine re-polarization of macrophages in mesotheliomas to an M1 phenotype could enhance efficacy of cytotoxic therapy. This work was supported by grants from the NCI and a DoD Mesothelioma Program grant PR080717 to Broaddus and Coussens Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3844.