IRF5: a rheostat for tumor‐infiltrating lymphocyte trafficking in breast cancer?

Abstract

Breast cancer (BC) development and progression is influenced by the intrinsic properties of tumor cells as well as their surrounding microenvironment. Cells found in the microenvironment include stroma cells, fibroblasts, endothelial cells, pericytes, adipocytes and various types of infiltrating immune cells. The immune infiltrate generally includes myeloid cells and lymphocytes (tumor infiltrating lymphocytes (TILs)) composed of B cells, T cells and natural killer cells. Recently, the immune response has been named as a new hallmark of cancer. In BC, the extent of lymphocyte infiltration is predictive for better local responses to neoadjuvant chemotherapy and prognostic for long-term disease-free survival. [1][2][3] However, little is known about the processes involved in attracting specific subsets of TIL to the tumor microenvironment.Pimenta and coworkers investigate the role of interferon regulatory factor 5 (IRF5) in regulating tumor infiltration. Previously, they demonstrated that IRF5, a transcription factor known to regulate type I interferon signaling and cytokines/chemokines with lymphocytechemotactic activities, was downregulated in advanced stages of BC and invasion/ metastasis. 4 Normal breast tissue and atypical ductal hyperplasia express IRF5, whereas only 38% of ductal carcinoma in situ and 10% invasive ductal carcinoma retain IRF5 expression detectable by immunofluorescence and immunohistochemistry.The metastatic lymph node tissues from invasive ductal carcinoma are negative for IRF5 expression. Knockdown assays have shown that IRF5 acts as a critical regulator for mammary epithelial cell growth and DNA damage via its regulation of CXCR4 expression. Moreover, mice inoculated with human BC cell lines, expressing IRF5 or not, support the ability of this transcription factor to inhibit in vivo tumor formation and in vitro metastasis/ invasion. Together, these data suggest that IRF5 acts as a tumor suppressor gene in BC with its regulation of pro-and antiinflammatory cytokine/chemokine expression helping to modify the tumor immune microenvironment.In this issue of Immunology and Cell Biology, Pimenta et al. 5 show that IRF5 is a novel and direct regulator of CXCL13 expression in mammary epithelial tumor cells. Exogenous expression of IRF5 in breast tumor cell lines lacking endogenous IRF5 induced the production and secretion of numerous cytokines and chemokines, including CXCL13, known to have important roles in the recruitment of specific immune cells to the tumor site. In particular, CD19 + CXCR5 + B cells and CD4 + CXCR5 + T cells were increasingly recruited in IRF5-tumor conditioned media (Figure 1). The authors employed a focused tumor-inflammatory gene array to quantify expression of 104 cytokine/chemokine and 83 receptor genes in MDA-MB-231 cells, a human triple negative breast carcinoma cell line, either lacking or expressing IRF5. These data reveal that IRF5 can modulate many pro-inflammatory and lymphocyte trafficking cytokines/chemokines (50% are upregulated ⩾ twofold). Four ligands, CXC...

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