CXCL14 Attenuates Triple-Negative Breast Cancer Progression by Regulating Immune Profiles of the Tumor Microenvironment in a T Cell-Dependent Manner.

Abstract

Triple-negative breast cancer (TNBC) is aggressive and has a poor overall survival due to a lack of therapeutic targets compared to other subtypes. Chemokine signature revealed that TNBC had low levels of CXCL14, an orphan homeostatic chemokine to regulate the immune network. Here, we investigated if CXCL14 plays a critical role in TNBC progression, focusing on survival rates, tumor growth and metastasis, and immune profiles in the tumor microenvironment. Analysis of human breast-cancer datasets showed that low CXCL14 expression levels were associated with poor survival rates in patients with breast cancer, particularly for TNBC subtypes. Overexpression of CXCL14 in TNBC 4T1 orthotopic mouse model significantly reduced tumor weights and inhibited lung metastasis. Furthermore, the CXCL14 overexpression altered immune profiles in the tumor microenvironment as follows: decreased F4/80+ macrophages and CD4+CD25+ Treg cells, and increased CD8+T cells in primary tumors; decreased Ly6C+ myeloid cells and CD4+CD25+ Treg cells and increased CD4+ and CD8+T cells in lung metastatic tumors. CXCL14-induced reduction of tumor growth and metastasis was diminished in T cell-deficient nude mice. Taken together, our data demonstrate that CXCL14 inhibits TNBC progression through altering immune profiles in the tumor microenvironment and it is mediated in a T cell-dependent manner. Thus, CXCL14 could be used as a biomarker for prognosis.