Abstract 4005: HDAC inhibitors regulate M2 tumor-associated macrophage function through histone acetylation

Abstract

Abstract Macrophage tumor infiltration in metastatic prostate cancer is a predictor of patient prognosis. Macrophages influence tumors in contrasting ways depending on their polarization: M1 macrophages have anti-tumor functions while M2 macrophages are pro-tumor. The external stimuli influencing macrophage differentiation and M2 polarization have been largely elucidated but the resulting downstream changes remain unknown. There are a number of epigenetic differences between M1 and M2 macrophages that act as important functional determinants. Recent work studying these epigenetic changes has implicated histone deacetylases (HDACs), as critical regulators in macrophage differentiation and in maintaining M1 or M2 function. Pan-HDAC inhibitors (HDIs) such as the clinically utilized suberanilohydroxamic acid (SAHA) target a wide range of HDACs and provide a means for manipulating macrophage histone acetylation. Though HDIs have been found to attenuate inflammatory functions in M1 macrophages, the field has yet to explore effects of histone acetylation in M2 macrophages. Using M2 macrophages derived from human CD14+ monocytes, we found that SAHA regulates M2 macrophage polarization and function through alteration of histone acetylation. Work is ongoing to test expression levels of canonical M2 markers such as the mannose receptor CD206 and scavenger receptor CD163 in M2 macrophages exposed to SAHA either during or after M2 polarization. Additionally, investigation into the ability of these populations to secrete M2 cytokines such as IL-10 and VEG-FA and induce EMT in prostate cancer cells is also being pursued. These results contribute to scientific knowledge of epigenetic regulation in macrophage function and elucidate strategies to decrease the pro-tumor function of tumor-infiltrating M2 macrophages. This work lays the foundation for using epigenetic regulators to modulate the tumor microenvironment and advance cancer medicine. Citation Format: Amber E. de Groot, Jelani C. Zarif, Kenneth J. Pienta. HDAC inhibitors regulate M2 tumor-associated macrophage function through histone acetylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4005. doi:10.1158/1538-7445.AM2017-4005