CCL5-Mediated Th2 Immune Polarization Promotes Metastasis in Luminal Breast Cancer
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...
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| Vydáno v: | Cancer research (Chicago, Ill.) Ročník 75; číslo 20; s. 4312 - 4321 |
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| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
15.10.2015
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| ISSN: | 1538-7445 |
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| 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. |
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| AbstractList | 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. |
| Author | Gong, Lei Gao, Wei-Qiang Zhang, Bing Zhang, Qianfei Qin, Jilong Zhang, Yan Zhong, Lin |
| Author_xml | – sequence: 1 givenname: Qianfei surname: Zhang fullname: Zhang, Qianfei organization: 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 – sequence: 2 givenname: Jilong surname: Qin fullname: Qin, Jilong organization: Department of Pathology, The First Affiliate Hospital of Guangzhou Medical University, Guangzhou, China – sequence: 3 givenname: Lin surname: Zhong fullname: Zhong, Lin organization: Yuhuangding Hospital, Yantai, China – sequence: 4 givenname: Lei surname: Gong fullname: Gong, Lei organization: Yuhuangding Hospital, Yantai, China – sequence: 5 givenname: Bing surname: Zhang fullname: Zhang, Bing organization: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts – sequence: 6 givenname: Yan surname: Zhang fullname: Zhang, Yan email: gao.weiqiang@sjtu.edu.cn, yanzh@sjtu.edu.cn organization: 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 – sequence: 7 givenname: Wei-Qiang surname: Gao fullname: Gao, Wei-Qiang email: gao.weiqiang@sjtu.edu.cn, yanzh@sjtu.edu.cn organization: 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 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26249173$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Animals Breast Neoplasms - genetics Breast Neoplasms - immunology Breast Neoplasms - metabolism Breast Neoplasms - pathology Case-Control Studies Cell Differentiation Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - metabolism Chemokine CCL5 - blood Chemokine CCL5 - deficiency Chemokine CCL5 - genetics Chemokine CCL5 - metabolism Disease Models, Animal Disease Progression DNA-Binding Proteins - genetics Female Gene Deletion Gene Expression Humans Interleukin-4 - genetics Interleukin-4 - metabolism Lung Neoplasms - secondary Mice Mice, Knockout Myeloid Cells - immunology Myeloid Cells - metabolism Neoplasm Metastasis Receptors, CCR3 - genetics Receptors, CCR3 - metabolism Signal Transduction Spheroids, Cellular T-Lymphocyte Subsets - cytology T-Lymphocyte Subsets - immunology T-Lymphocyte Subsets - metabolism Th2 Cells - cytology Th2 Cells - immunology Th2 Cells - metabolism Transcription Factors - genetics Tumor Cells, Cultured |
| Title | CCL5-Mediated Th2 Immune Polarization Promotes Metastasis in Luminal Breast Cancer |
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