Abstract 454: Targeting macrophages in a preclinical model of malignant mesothelioma

Abstract

Abstract Malignant pleural mesothelioma (MPM) is a debilitating, incurable cancer that exhibits a high degree of resistance to standard chemotherapy; thus, we sought to identify novel therapeutic targets for treatment. In the vast majority of cases, MPM is associated with exposure to asbestos fibers, which result in a chronic pro-inflammatory state. As such, we hypothesized that MPMs were infiltrated by leukocytes possessing tumor-potentiating activities. To address this, we evaluated MPMs, resected from 26 patients, by flow cytometry and found that tumors were highly infiltrated with macrophages (31 ± 4.6% of total CD45+), a percentage that is significantly higher that that observed in other thoracic malignancies (NSCLC cancer, 9%; esophageal, 4%). Since recent experimental data has revealed that tumor-associated macrophages (TAMs) secrete proangiogenic, prosurvival, and proinvasive factors that foster tumor progression, we evaluated macrophage-depletion in MPM as a novel therapeutic strategy. Using a syngeneic murine transplantation model and liposomal-encapsulated clodronate that efficiently deplete phagocytic macrophages, as monotherapy, and in combination with chemotherapy, we revealed a significant decrease in tumor growth and a decrease in tumor-burden in tumor-bearing mice depleted of macrophages. Furthermore, when macrophage-depletion was combined with the cytotoxic agents gemcitabine and TRAIL, an even greater reduction in tumor burden was observed as compared to mice treated with either agent alone. These studies indicate that: 1) mesothelioma-associated macrophages provide a protumor function, and 2) depletion of mesothelioma-associated macrophages may improve efficacy of cytotoxic chemotherapy. Ongoing studies to reveal the effect of macrophage-depletion plus chemotherapy in limiting MPM development in NF2ko/+ mice exposed to asbestos are underway. This work was supported by an NIH T32 training grant to Dr. Blakely, and by a DoD Mesothelioma Program grant (PR080717) to Drs. Broaddus and Coussens. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 454. doi:10.1158/1538-7445.AM2011-454