Tumors expressing ACKR1 exhibit a unique signature of tumor-infiltrating immune cells in women with breast cancer.
Jenkins BD, Fleifel T, Martini R, Ali H, Newman L, and Davis M. Tumors expressing ACKR1 exhibit a unique signature of tumor-infiltrating immune cells in women with breast cancer. Cancer Immunol Res 2019; 7(2).
Cancer Immunol Res
Tumor associated immune cells, stroma and several other cell types make up the complex tumor microenvironment (TME) that contributes to a broad spectrum of potential clinical outcomes for breast cancer (BC) patients. Part of this delicate interplay is the interaction between proinflammatory chemokines and their receptors, which direct the migration of immune cells to areas of tumor-associated inflammation. Our focus in this complex process is on the role of the Atypical Chemokine Receptor 1 (ACKR1/DARC). In general immune response, its expression on erythrocytes helps to maintain chemokine homeostasis by sequestering chemokines in circulation while its expression on endothelial tissue transcytoses the chemokines from tissue into circulation, which ultimately affects which immune cells are brought to the TME. Its role in epithelial tissue expression is less understood. The purpose of this study is to investigate differential gene expression of ACKR1 in breast epithelial tumor tissue through IHC methods, and to determine how that expression correlates with both circulating and infiltrating proinflammatory chemokines. In addition, we will show this role to be associated with specific classes of tumor-infiltrating lymphocytes (TIL) in BC. Circulating chemokine levels for a variety of ACKR1-associated proinflammatory chemokines were determined using Luminex multiplexing assays. Results from our study cohort indicate differential expression of ACKR1 on epithelial tumor tissue, which correlated with a unique signature of immune cell infiltrates and associated proinflammatory chemokines. Tumors positive for AKCR1 expressed higher levels of circulating and infiltrating CCL2 (MCP-1) and lower levels of CXCL8 (IL-8). Tumorexpressing ACKR1 was also found to be associated with T-cells, B-cells, macrophages, and monocytes, where positive tumors tended to express a more robust profile of TILs. Our preliminary data suggest the presence or absence of ACKR1 on breast epithelial tumor tissue can influence the chemokine and immune cell profile within the TME, which can ultimately influence tumor aggressiveness, proliferation, and response to treatments, such as immunotherapies.