title: CCL5-Mediated Th2 Immune Polarization Promotes Metastasis in Luminal Breast Cancer.
abstract: The tumor-promoting chemokine CCL5 has been implicated in malignant transformation of breast epithelial cells, with studies to date focusing mainly on basal-type breast cancers. In this study, we investigated the consequences of CCL5 deletion in the MMTV-PyMT transgenic mouse model of luminal breast cancer. In this model, primary tumor burden and pulmonary metastases were reduced significantly in CCL5-deficient subjects, an effect found to be associated with a deficit of Th2 (IL4⁺CD4⁺ T) cells. Mechanistic investigations revealed that CCL5 activates CCR3, a highly expressed chemokine receptor on CD4⁺ T cells, and also boosts Gfi1 expression to promote the differentiation of Th2 cells, which enhance the prometastatic activity of tumor-associated myeloid cells. Clinically, polarization toward this immunosuppressive Th2 phenotype was also evident in patients with advanced luminal breast cancer. Thus, our findings showed that CCL5/CCR3 signaling promotes metastasis by inducing Th2 polarization of CD4⁺ T cells, with implications for prognosis and immunotherapy of luminal breast cancer.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Qianfei
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Pathology, The First Affiliate Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Jilong
authors.initials: J
authors.lastname: Qin
authors.affiliation: Yuhuangding Hospital, Yantai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Yuhuangding Hospital, Yantai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Gong
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. gao.weiqiang@sjtu.edu.cn yanzh@sjtu.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. Collarative Innovation Center of Systems Biomedicine, Sanghai, China. gao.weiqiang@sjtu.edu.cn yanzh@sjtu.edu.cn.
authors.forename: Wei-Qiang
authors.initials: WQ
authors.lastname: Gao
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D018946:Chemokine CCL5 / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D009362:Neoplasm Metastasis; D054397:Receptors, CCR3 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D018946:Chemokine CCL5; D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; D054397:Receptors, CCR3; D014157:Transcription Factors; D015847:Interleukin-4