Abstract 4723: Macrophages foster neoplastic progression of malignant mesothelioma and limit response to chemotherapy.

Abstract

Abstract We, and others, have previously reported that macrophages infiltrating mammary adenocarcinomas foster late-stage cancer progression1-3, and that targeted therapies diminishing macrophage presence in tumors, and improve response to standard chemotherapy (CTX) resulting in slowed primary tumor growth, reduced pulmonary metastasis and increased overall survival (OS) of tumor-bearing mice4,5. These experimental studies correlate with clinical findings indicating that high densities of CD68+ myeloid cells correlate with reduced OS in patients with breast cancer6. Malignant mesotheliomas (MM), a rare cancer that can develop as a result of prior asbestos exposure, is highly resistant to conventional cytotoxic therapy7, and in the pleural space is associated with significant densities of macrophages that also correlate with decreased OS8. To investigate a functional role for macrophages in fostering neoplastic progression of MM, and/or in limiting response to CTX, we investigated the efficacy of several antagonists targeting the colony stimulating factor-1 (CSF1)/CSF-1 receptor (CSF1-R) CSF-1R signaling cascade to reveal the functional significance of macrophages in MM, and to determine if this class of agents exhibited efficacy as monotherapy, or in combination with CTX, to improve OS of tumor-bearing mice. Using a syngeneic orthotopic mouse model for MM, our results indicate that reducing the presence of macrophages in MM significantly slows early, as well as late-stage MM growth, and improves response to standard-of-care CTX. These experimental findings indicate a protumoral role for macrophages in MM, and support clinical investigation of targeted therapies, in combination with CTX, for treatment of patients with MM. 1. Lin et al., J Exp Med 193, 727-740 (2001). 2. DeNardo et al., Cancer Cell 16, 91-102 (2009). 3. Gocheva et al., Genes Dev 24, 241-255 (2010). 4. DeNardo et al., Cancer Discov 1, 54-67 (2011). 5. Shree et al., Genes and Development in press(2011). 6. Campbell et al., Breast Cancer Res Treat 128, 703-711 (2011). 7. Sugarbaker et al., Expert Rev Respir Med 4, 363-372 (2010). 8. Burt et al., Cancer 117, 5234-5244 (2011). The authors acknowledge generous support from the NIH/NCI, Dept of Defense (DoD) Era of Hope Scholar Award Expansion Award, Susan G. Komen Fndt, Breast Cancer Research Fndt, and an Investigator-Initiated Research Award in Mesothelioma from the DoD. Citation Format: Collin Blakely, Tina Bose, Melissa Wheeler, Raphael Bueno, David Sugarbaker, David Jablons, V. Courtney Broaddus, Lisa Coussens. Macrophages foster neoplastic progression of malignant mesothelioma and limit response to chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4723. doi:10.1158/1538-7445.AM2013-4723