Recruited monocytic myeloid-derived suppressor cells promote the arrest of tumor cells in the premetastatic niche through an IL-1[beta]-mediated increase in E-selectin expression

The tumor premetastatic niche initiated by primary tumors is constructed by multiple molecular factors and cellular components and provides permissive condition that allows circulating tumor cells to successfully metastasize. Myeloid-derived suppressor cells (MDSCs), a population of immature cells in pathological conditions, play a critical role in the formation of the premetastatic niche. However, few researches are focused on the function of monocytic MDSCs (mo-MDSCs), a subtype of MDSCs, in the construction of the niche. Here, we show that the number of mo-MDSCs is significantly increased in the premetastatic lungs of tumor-bearing mice, thus promoting tumor cell arrest and metastasis. Before the arrival of tumor cells, the lung-recruited mo-MDSCs produced IL-1[beta], thereby increasing E-selectin expression and promoting tumor cell arrest on endothelial cells. Depletion of mo-MDSCs in the premetastatic lungs decreased IL-1[beta] production, resulting in reduced E-selectin expression. In addition, compared with alveolar macrophages and interstitial macrophages, mo-MDSCs were the major source of IL-1[beta] expression in the premetastatic lungs. Cytokine array analyses and transwell experiments revealed that CCL12 recruits mo-MDSCs to premetastatic lungs. CCL12 knockdown in tumor-bearing mice significantly decreased mo-MDSC infiltration into the premetastatic lungs, leading to reduced E-selectin expression. Overall, the permissive conditions produced by the infiltrated mo-MDSCs correlated with increased tumor cell arrest and metastasis. These results reveal a novel role of mo-MDSCs in constructing the premetastatic niche. Thus, inhibition of mo-MDSCs infiltration may change the premetastatic niche to normal condition and attenuate tumor metastasis. What's new? During premetastasis, the tissue microenvironment of distant metastatic target organs is altered to permit habitation for circulating tumor cells. Premetastatic niche formation is influenced by granulocytic myeloid-derived suppressor cells (G-MDSCs), but according to this study, the other major MDSC subtype, monocytic MDSCs (mo-MDSCs), hitherto unknown factors in premetastatic niche construction, are also critical. In tumor-bearing mice, mo-MDSCs were greatly increased in premetastatic lung tissue, where they produced IL-1[beta], thereby promoting E-selectin expression and subsequent tumor cell adhesion to the vascular endothelium. Lung infiltration by mo-MDSCs was significantly decreased via knockd