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.
©2015 American Association for Cancer Research.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / immunology*
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Case-Control Studies
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Cell Differentiation
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Chemokine CCL5 / blood
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Chemokine CCL5 / deficiency
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Chemokine CCL5 / genetics
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Chemokine CCL5 / metabolism*
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DNA-Binding Proteins / genetics
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Disease Models, Animal
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Disease Progression
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Female
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Gene Deletion
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Gene Expression
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Humans
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Interleukin-4 / genetics
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Interleukin-4 / metabolism
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Lung Neoplasms / secondary
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Mice
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Mice, Knockout
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Myeloid Cells / immunology
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Myeloid Cells / metabolism
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Neoplasm Metastasis
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Receptors, CCR3 / genetics
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Receptors, CCR3 / metabolism
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Signal Transduction
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Spheroids, Cellular
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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Th2 Cells / cytology
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Th2 Cells / immunology*
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Th2 Cells / metabolism*
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Transcription Factors / genetics
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Tumor Cells, Cultured
Substances
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Chemokine CCL5
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DNA-Binding Proteins
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GFI1 protein, human
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Receptors, CCR3
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Transcription Factors
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Interleukin-4