Slit2在各种癌症中发挥抗肿瘤作用;然而,潜在的机制,尤其是它在调节免疫中的作用,尤其是在骨髓壁龛中,系统仍然未知。阐明巨噬细胞在肿瘤进展中的行为可以潜在地改善免疫疗法。使用自发性乳腺肿瘤病毒启动子-多瘤中T抗原(PyMT)乳腺癌小鼠模型,我们观察到Slit2在体外分化后增加了骨髓中抗肿瘤M1巨噬细胞的丰度。此外,用Slit2处理的骨髓同种异体移植物注射的骨髓切除的PyMT小鼠显示肿瘤生长明显减少,增强了M1巨噬细胞在其肿瘤基质中的募集。机制研究表明,Slit2显着增强了骨髓源性巨噬细胞(BMDM)的糖酵解并减少了脂肪酸氧化。Slit2治疗还改变了从健康人血液中分离的巨噬细胞中的线粒体呼吸代谢物,这些巨噬细胞用乳腺癌患者的血浆进行了治疗。总的来说,这项研究,第一次,显示Slit2通过调节免疫代谢增加BMDM向抗肿瘤表型的极化。此外,这项研究提供的证据表明,可溶性Slit2可以作为新的治疗策略,以增强抗肿瘤免疫应答。
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.