LSC - 2017 - Re-education of tumor-associated macrophages by modulating histone deacetylases in lung cancer

Abstract

Background: Tumor microenvironment plays pivotal role in progression and metastasis of lung cancer. Within the established tumor microenvironment, tumor-associated macrophages (TAMs) are one of the most abundant stromal cell types. M1 macrophages possess anti-tumor capability and M2 macrophages manifest pro-tumor feature. Objectives: This study investigated epigenetic mechanisms of macrophages polarization and re-education of TAMs by HDACs. Methods: Human naive macrophages were generated from peripheral blood mononuclear cells and were polarized to M1 or M2 macrophages. Additionally, M0 macrophages and lung cancer cells were co-cultured for 3-5 days to generate TAMs. Results: Both in vivo and in vitro, M2 macrophages led to increased tumor cell proliferation, migration and decreased apoptosis. RNA-Seq analysis showed that HDAC2 was significantly upregulated in M2 macrophages. Furthermore, upregulation of HDAC2 at protein level and significantly elevated HDAC activity was observed in M2 macrophages and M2-like TAMs. Interestingly, suppression of HDAC2 employing pharmacological (HDAC inhibitors: SAHA, VPA) or genetic (HDAC2-siRNA) approaches in M2 macrophages and as well as in isolated TAMs from human- and mouse- lung tumors, led to upregulation of M1 markers (TNFa, IL8, CCR7, IL12) and downregulation of M2 markers (IL10, ALOX15, CD206), which can also reverse tumor cells functions. In addition, RNA-seq from HDAC2-knockdown M2 macrophages leads to identification of target genes that are involved in macrophage repolarization processes. Conclusions: Suppression of HDAC2 switches M2-like TAMs into M1-like phenotype and regulates tumor cell functions. Modulation of HDAC2 may provide a novel strategy for TAMs repolarization and cancer therapy.