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 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 on CD4+ T cells, and also boosts Gfi1 expression to promote the differentiation of Th2 cells which enhance the pro-metastatic activity of tumor-associated myeloid cells. Clinically, polarization towards 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.