PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway

Rui Zhang; Mengxue Dong; Juchuanli Tu; Fengkai Li; Qiaodan Deng; Jiahui Xu; Xueyan He; Jiajun Ding; Jie Xia; Dandan Sheng; Zhaoxia Chang; Wei Ma; Haonan Dong; Yi Zhang; Lixing Zhang; Lu Zhang; Suling Liu

doi:10.1038/s41392-023-01337-3

PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway

Signal Transduct Target Ther. 2023 Mar 1;8(1):97. doi: 10.1038/s41392-023-01337-3.

Authors

Rui Zhang^#¹, Mengxue Dong^#¹, Juchuanli Tu¹, Fengkai Li¹, Qiaodan Deng¹, Jiahui Xu¹, Xueyan He¹, Jiajun Ding^{1

2}, Jie Xia¹, Dandan Sheng¹, Zhaoxia Chang¹, Wei Ma¹, Haonan Dong¹, Yi Zhang³, Lixing Zhang¹, Lu Zhang⁴, Suling Liu^{5

6}

Affiliations

¹ Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China.
² Breast Surgery, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
³ Department of Breast and Thyroid Surgery, Southwest Hospital, the First Affiliated Hospital of the Army Military Medical University, Chongqing, 400038, China.
⁴ Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China. zlu7025@gmail.com.
⁵ Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai, 200032, China. suling@fudan.edu.cn.
⁶ Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, China. suling@fudan.edu.cn.

^# Contributed equally.

Abstract

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 CCL20^high-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 CCL20^high-expressing breast cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms*
Cell Differentiation
Cell Line, Tumor
Chemokines*
Humans
Ligands
Myeloid-Derived Suppressor Cells*
Neoplastic Stem Cells*
Receptors, Interleukin-8B

Substances

Chemokines
Ligands
Receptors, Interleukin-8B