Abstract
Slit2 exerts antitumor effects in various cancers; however, the underlying mechanism, especially its role in regulating the immune, especially in the bone marrow niche, system is still unknown. Elucidating the behavior of macrophages in tumor progression can potentially improve immunotherapy. Using a spontaneous mammary tumor virus promoter-polyoma middle T antigen (PyMT) breast cancer mouse model, we observed that Slit2 increased the abundance of antitumor M1 macrophage in the bone marrow upon differentiation in vitro. Moreover, myeloablated PyMT mice injected with Slit2-treated bone marrow allografts showed a marked reduction in tumor growth, with enhanced recruitment of M1 macrophage in their tumor stroma. Mechanistic studies revealed that Slit2 significantly enhanced glycolysis and reduced fatty acid oxidation in bone marrow-derived macrophages (BMDMs). Slit2 treatment also altered mitochondrial respiration metabolites in macrophages isolated from healthy human blood that were treated with plasma from breast cancer patients. Overall, this study, for the first time, shows that Slit2 increases BMDM polarization toward antitumor phenotype by modulating immune-metabolism. Furthermore, this study provides evidence that soluble Slit2 could be developed as novel therapeutic strategy to enhance antitumor immune response.
Highlights
Slit2, a secretory glycoprotein originally discovered for its role in neuronal guidance, is frequently reported to be deactivated by promoter methylation in several cancers, including breast cancer [1,2,3,4]
While tumors from Slit2-treated mice only showed a trend in decrease in the M2 macrophage population, M1 macrophages identified as CD45+F4/80+CD38+ cells were significantly more abundant in mice with Slit2-treated tumors compared to phosphate-buffered saline (PBS)-treated tumors (71 ± 20 vs. 188 ± 81.4 cells in 20,000 events, n = 4, *p < 0.05) (Figure 1B)
To assess whether Slit2 manipulates macrophage polarization by affecting glycolysis, we investigated the rate of glycolysis in bone marrowderived macrophages (BMDMs) isolated from PBS- and Slit2-treated WT and polyoma middle T antigen (PyMT) mouse bone marrows using Seahorse Bioanalyzer
Summary
A secretory glycoprotein originally discovered for its role in neuronal guidance, is frequently reported to be deactivated by promoter methylation in several cancers, including breast cancer [1,2,3,4]. Slit2/ROBO1 signaling is reported to exert antitumor activity [5, 6]. Slit Induces Antitumor Activity via Immunometabolism metastasis, whereas Slit deletion in the tumor enhanced metastasis significantly [8]. Another recent study describes the role of Slit in inhibiting macropinocytosis [9]. Slit has been shown to inhibit breast cancer by enhancing phagocytosis and reducing fibrosis [10]. These studies suggest that Slit may play different roles in different cell types. The underlying mechanism by which Slit regulates immune cell metabolism, and its subsequent impact on breast tumor growth, has not been elucidated
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