The Functional Role of Atypical Chemokine Receptor 1 in Immune Cell Regulation of Breast Cancer
Jenkins BD, Martini R, Gardner K, Monteil M, Deeb D, Newman L, and Davis M. The Functional Role of Atypical Chemokine Receptor 1 in Immune Cell Regulation of Breast Cancer. Cancer Res 2019; 79(13).
Breast cancer (BC) is a heterogeneous disease that leads to varied molecular subtypes and distinct clinical outcomes. Tumor heterogeneity, which is in part influenced by genetic ancestry, contributes to racial disparities in BC. This disparity has persisted for over 30 years, despite improvements in detection, screening, and treatment methods. When investigating race-specific differences in the breast tumor microenvironment (TME), we believe that chemokine receptors, such as atypical chemokine receptor 1 (ACKR1/DARC), play an integral role in regulating chemokine and immune cell migration in circulation and the TME, ultimately influencing tumor progression. ACKR1/DARC specifically plays a role in ancestry-related differences in BC due to an African-specific ancestral allele (“Duffy-null” mutation) that is fixed in Sub-Saharan African populations, and present in 60-70% of African-Americans. Those that harbor the mutation do not express ACKR1/DARC on erythrocytes, ultimately affecting immune cell migration in these populations only. To better understand the effects of this variant in circulation and the TME, we performed immunohistochemistry (IHC) on breast tumors from a cohort of patients with matched blood samples. From our IHC analysis, we quantified levels of ACKR1/DARC, in addition to levels of target pro-inflammatory chemokines, and distinct immune populations of T-cells and macrophages. In addition, individuals were genotyped to determine Duffy-null status, and a correlative Luminex multiplex assay was performed on patient plasma to determine concentrations of pro-inflammatory chemokines in circulation. We determined that those with low expression of ACKR1/DARC in tumors exhibited a unique signature of immune cell infiltrates that would encourage a more aggressive TME. In addition, we observed variable levels of circulating chemokines, where those with the Duffy-null mutation exhibited significantly decreased levels of CCL2. Overall, our analyses support the hypothesis that tumor-specific DARC/ACKR1 plays a vital role in immune cell regulation in women with BC.