Certain immune cells and inflammatory cytokines are essential components in the tumor microenvironment to promote breast cancer progression. Among them, macrophages are important immune components in all tissues, where tumor-associated macrophages (TAMs) are the predominant population of tumor-infiltrating immune cells. The presence of TAMs in breast cancer is associated with poor prognosis and correlates with drug resistance. In TME, TAMs promote cancer progression by participating in tumor growth, angiogenesis, cell invasion, cell survival, and immune suppression. Specifically, TAMs secrete matrix metalloproteinases (MMPs), serine proteases, and cathepsins to disrupt cell-cell junctions facilitating cancer cells’ intravasation and extravasation. On the other hand, TAMs mediate immunosuppression through either expressing high levels of T cell immune checkpoint ligands, such as PDL1, PDL2, CD80, or CD86, to directly inhibit T cells, or releasing cytokines that contribute to the maintenance of immunosuppressive TME. In this project, we aimed to identify key players involved in the cross-talk between breast cancer cells and TAMs. Once we figure out a way to disrupt their crosstalk, targeting the key player may be a novel therapeutic approach for immune cancer therapy.
Ongoing Project: Monocytes secrete CXCL7 to promote breast cancer progression
Chemokines are important mediators for immune cell trafficking and differentiation. In the TME, different immune cells are recruited and further differentiated via interactions between chemokines and chemokine receptors. To identify key immune players in the tumor microenvironment, we applied highly invasive MDA-MB-231 breast cancer cell lines to co-culture with human monocyte THP-1 cells and identified CXCL7 by cytokine array as one of the increasingly secreted cytokines by THP-1 cells. Further investigations indicated that upon co-culturing, breast cancer cells secreted CSF1 to induce expression and release of CXCL7 from monocytes, which in turn acted on cancer cells to promote FAK activation, MMP13 expression, migration, and invasion. In a xenograft mouse model, administration of CXCL7 antibodies significantly reduced the abundance of M2 macrophages in TME as well as decreased tumor growth and distant metastasis. The clinical investigation further suggested that high CXCL7 expression is correlated with breast cancer progression and poor overall survival of patients. Overall, our study unveils an important immune cytokine, CXCL7, which is secreted by tumor-infiltrating monocytes, to stimulate cancer cell migration, invasion, and metastasis, contributing to the promotion of breast cancer progression.
