我们先前的研究已经表明，C-C模体趋化因子配体20(CCL20)通过正向调节乳腺癌干细胞(BCSC)的自我更新，促进了肿瘤的进展并增强了癌细胞的化疗耐药性。然而，CCL20是否通过改变肿瘤微环境(TME)来影响乳腺癌的进展仍不清楚。在这里，我们观察到多形核中性粒细胞衍生的抑制细胞(PMN-MDSCs)在CCL20过表达的癌细胞异种移植肿瘤的TME中明显富集。机制上，CCL20通过其受体C-C模式趋化因子受体6(CCR6)激活粒-单核祖细胞(GMPs)的分化，导致PMN-MDSCs的扩张。来自CCL20过表达的癌细胞异种移植肿瘤的PMN-MDSCs(被CCL20调节的PMN-MDSCs)分泌大量C-X-C模体趋化因子配体2(CXCL2)，并通过激活CXCR2/ NOTCH1/HEY1信号通路增加ALDH+BCSCs。此外，C-X-C模体趋化因子受体2(CXCR2)拮抗剂SB225002通过降低CCL20高表达肿瘤中的BCSCs，增强了多西他赛(DTX)对肿瘤生长的影响。这些发现阐明了CCL20如何调节TME促进癌症发展，表明在乳腺癌中干扰PMN-MDSCs和BCSCs之间的相互作用，特别是在CCL20高表达的乳腺癌中，存在一种新的治疗策略。©2023年作者。

Our previous studies have showed that C-C motif chemokine ligand 20 (CCL20) advanced tumor progression and enhanced the chemoresistance of cancer cells by positively regulating breast cancer stem cell (BCSC) self-renewal. However, it is unclear whether CCL20 affects breast cancer progression by remodeling the tumor microenvironment (TME). Here, we observed that polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were remarkably enriched in TME of CCL20-overexpressing cancer cell orthotopic allograft tumors. Mechanistically, CCL20 activated the differentiation of granulocyte-monocyte progenitors (GMPs) via its receptor C-C motif chemokine receptor 6 (CCR6) leading to the PMN-MDSC expansion. PMN-MDSCs from CCL20-overexpressing cell orthotopic allograft tumors (CCL20-modulated PMN-MDSCs) secreted amounts of C-X-C motif chemokine ligand 2 (CXCL2) and increased ALDH+ BCSCs via activating CXCR2/NOTCH1/HEY1 signaling pathway. Furthermore, C-X-C motif chemokine receptor 2 (CXCR2) antagonist SB225002 enhanced the docetaxel (DTX) effects on tumor growth by decreasing BCSCs in CCL20high-expressing tumors. These findings elucidated how CCL20 modulated the TME to promote cancer development, indicating a new therapeutic strategy by interfering with the interaction between PMN-MDSCs and BCSCs in breast cancer, especially in CCL20high-expressing breast cancer.© 2023. The Author(s).