ABSTRACT
High infiltration of M2-polarized macrophages in the primary tumor indicates unfavorable prognosis and poor overall survival in the patients with triple-negative breast cancer (TNBC). Thus, reversing M2-polarized tumor-associated macrophages in the tumors has been considered as a potential therapeutic strategy for TNBC. Sphingomyelin synthase 2 (SMS2) is the key enzyme for sphingomyelin production, which plays an important role in plasma membrane integrity and function. In this study we investigated whether SMS2 inhibitor or SMS2 gene knockout could reduce macrophages M2 polarization and tumor progression in a mouse model of TNBC. We showed that SMS2 mRNA expression was linked to immunosuppressive tumor microenvironment and poor prognosis in TNBC patients. The knockout of SMS2 or application of 15w (a specific SMS2 inhibitor) markedly decreased the generation of M2-type macrophages in vitro, and reduced the tumor weight and lung metastatic niche formation in a 4T1-TNBC mouse model. We further demonstrated that the in vivo antitumor efficacy of 15w was accompanied by a multifaceted remodeling of tumor immune environment reflecting not only the suppression of M2-type macrophages but also diminished levels of regulatory T cells and myeloid-derived suppressor cells leading to a dramatically improved infiltration of antitumor CD8+ T lymphocytes. Collectively, our results reveal a novel and important role of SMS2 in the protumorigenic function and may offer a new strategy for macrophage-targeted anticancer therapy.
Subject(s)
Macrophages/metabolism , Transferases (Other Substituted Phosphate Groups)/metabolism , Triple Negative Breast Neoplasms/physiopathology , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/metabolism , Cell Line, Tumor , Disease Progression , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Female , Gene Knockout Techniques , Humans , Immunity, Cellular/drug effects , Isoxazoles/pharmacology , Isoxazoles/therapeutic use , Macrophage Activation/drug effects , Macrophage Activation/physiology , Macrophages/drug effects , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Prognosis , Transferases (Other Substituted Phosphate Groups)/antagonists & inhibitors , Transferases (Other Substituted Phosphate Groups)/genetics , Triple Negative Breast Neoplasms/diagnosis , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/immunologyABSTRACT
Sphingomyelin synthase (SMS) is a key enzyme in sphingomyelin biosynthetic pathway, whose activity is highly related to the atherosclerosis progression. SMS2 could serve as a promising therapeutic target for atherosclerosis. Based on the structure of lead compound D2, a series of oxazolopyridine derivatives were designed, synthesized, and their inhibitory activities against purified SMS1 and SMS2 enzymes were evaluated respectively. The representative molecules QY4 and QY16 possess micromolar inhibitory activities against SMS2 and excellent isoform preferences over SMS1, qualified to be selected as potential molecules in further discovery of specific SMS2 inhibitors.
