Sphingomyelin synthase 2 facilitates M2-like macrophage polarization and tumor progression in a mouse model of triple-negative breast cancer

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.

Prognostic Value and Immune Infiltrates of ABCA8 and FABP4 in Stomach Adenocarcinoma

“…Previous findings have shown that immune cell infiltration is related to the prognosis of STAD [ 1 , 13 ]. A number of studies have shown that high infiltration of M2 macrophages indicates poor prognosis [ 1 , 37 – 39 ]. In Cervical Cancer, FABP4 was considered to be correlated to immune cell infiltration [ 40 ].…”

Magnetism-mediated targeting hyperthermia-immunotherapy in “cold” tumor with CSF1R inhibitor

“…CSF1/CSF1R signaling is crucial for the differentiation of mononuclear cells, especially macrophages, and maintains the immunosuppressive and protumor functions of tumor-associated macrophages (TAMs) 18 . TAMs are abundant in the tumor microenvironment and characterized by CSF1R overexpression, and promote tumor growth and metastasis, as well as suppress cytotoxic T lymphocytes 19 , 20 . Besides, CSF1R is also expressed in DCs, neutrophils, and myeloid-derived suppressor cells (MDSCs), and its expression is often associated with the diminished survival of cancer patients 21 - 23 .…”

Ceramide Metabolism Enzymes—Therapeutic Targets against Cancer

“…Furthermore, the inhibition with D609 diminishes the anticancer effect [ 118 ]. Recently, SMS2 was found to be upregulated in different cancers, such as breast [ 119 ] and ovarian [ 120 ]. High infiltration of M2-polarized macrophages in primary tumors is related with poor outcomes in patients.…”

“…By contrast, inhibition of SMS2 by specific siRNA led to accumulation of Cer and the promotion of cell death [ 121 ]. In addition, recent works observed that SMS2 is upregulated in breast cancer and induces macrophages polarization and tumor progression [ 119 ]. Moreover, SMS2 inhibition by 15w or knockdown reduced the release of cytokines that stimulate macrophage polarization, reducing tumor growth [ 119 ].…”

“…In addition, recent works observed that SMS2 is upregulated in breast cancer and induces macrophages polarization and tumor progression [ 119 ]. Moreover, SMS2 inhibition by 15w or knockdown reduced the release of cytokines that stimulate macrophage polarization, reducing tumor growth [ 119 ]. In addition, SMS1 down regulation was found in metastatic melanoma patients and was associated with worse prognosis due to an imbalance between SM and glucosyl-ceramide levels [ 122 ].…”