CCL5-Mediated Th2 Immune Polarization Promotes Metastasis in Luminal Breast Cancer

Cancer Res. 2015 Oct 15;75(20):4312-21. doi: 10.1158/0008-5472.CAN-14-3590. Epub 2015 Aug 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal
  • Disease Progression
  • 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

Substances

  • Chemokine CCL5
  • DNA-Binding Proteins
  • GFI1 protein, human
  • Receptors, CCR3
  • Transcription Factors
  • Interleukin-4