The immune microenvironment in inflammatory breast cancer (IBC) is poorly characterised, and molecular and cellular pathways that control accumulation of various immune cells in IBC tissues remain largely unknown. Here, we discovered a novel pathway linking the expression of the tetraspanin protein CD151 in tumour cells with increased accumulation of macrophages in cancerous tissues. It is notable that elevated expression of CD151 and a higher number of tumour-infiltrating macrophages correlated with better patient responses to chemotherapy. Accordingly, CD151-expressing IBC xenografts were characterised by the increased infiltration of macrophages. In vitro migration experiments demonstrated that CD151 stimulates the chemoattractive potential of IBC cells for monocytes via mechanisms involving midkine (a heparin-binding growth factor), integrin α6β1, and production of extracellular vesicles (EVs). Profiling of chemokines secreted by IBC cells demonstrated that CD151 increases production of midkine. Purified midkine specifically stimulated migration of monocytes, but not other immune cells. Further experiments demonstrated that the chemoattractive potential of IBC-derived EVs is blocked by anti-midkine antibodies. These results demonstrate for the first time that changes in the expression of a tetraspanin protein by tumour cells can affect the formation of the immune microenvironment by modulating recruitment of effector cells to cancerous tissues. Therefore, a CD151-midkine pathway can be considered as a novel target for controlled changes of the immune landscape in IBC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

中文翻译：

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CD151-midkine途径调节炎症性乳腺癌的免疫微环境。

炎症性乳腺癌（IBC）的免疫微环境的特征很差，控制IBC组织中各种免疫细胞积累的分子和细胞途径仍然未知。在这里，我们发现了一条新途径，将肿瘤细胞中四跨膜蛋白CD151的表达与癌组织中巨噬细胞的积累增加联系起来。值得注意的是，CD151的表达升高和大量的肿瘤浸润巨噬细胞与患者对化学疗法的反应更好有关。因此，表达CD151的IBC异种移植物以巨噬细胞浸润增加为特征。体外迁移实验表明，CD151可通过涉及中期因子（肝素结合生长因子）的机制刺激IBC细胞对单核细胞的化学吸引力，整合素α6β1，以及细胞外囊泡（EVs）的产生。对IBC细胞分泌的趋化因子进行分析表明，CD151增加了中因子的产生。纯化的中期因子特异性刺激单核细胞迁移，但不刺激其他免疫细胞迁移。进一步的实验表明，IBC衍生的电动汽车的化学吸引潜力被抗中期因子抗体阻断。这些结果首次证明肿瘤细胞四跨膜蛋白表达的变化可通过调节效应细胞向癌组织的募集而影响免疫微环境的形成。因此，CD151-midkine途径可被视为IBC中免疫格局受控变化的新靶标。©2020英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版 和细胞外囊泡（EVs）的生产。对IBC细胞分泌的趋化因子进行分析表明，CD151增加了中因子的产生。纯化的中期因子特异性刺激单核细胞迁移，但不刺激其他免疫细胞迁移。进一步的实验表明，IBC衍生的电动汽车的化学吸引潜力被抗中期因子抗体阻断。这些结果首次证明肿瘤细胞四跨膜蛋白表达的变化可通过调节效应细胞向癌组织的募集而影响免疫微环境的形成。因此，CD151-midkine途径可被视为IBC中免疫格局受控变化的新靶标。©2020英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版 和细胞外囊泡（EVs）的生产。对IBC细胞分泌的趋化因子进行分析表明，CD151增加了中因子的产生。纯化的中期因子特异性刺激单核细胞迁移，但不刺激其他免疫细胞迁移。进一步的实验表明，IBC衍生的电动汽车的化学吸引潜力被抗中期因子抗体阻断。这些结果首次证明肿瘤细胞四跨膜蛋白表达的变化可通过调节效应细胞向癌组织的募集而影响免疫微环境的形成。因此，CD151-midkine途径可被视为IBC中免疫格局受控变化的新靶标。©2020英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版