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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Veröffentlicht in:Cancer research (Chicago, Ill.) Jg. 75; H. 20; S. 4312 - 4321
Hauptverfasser: Zhang, Qianfei, Qin, Jilong, Zhong, Lin, Gong, Lei, Zhang, Bing, Zhang, Yan, Gao, Wei-Qiang
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 15.10.2015
Schlagworte:
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
ISSN:1538-7445
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1538-7445
DOI:10.1158/0008-5472.CAN-14-3590