Atypical Chemokine Receptor 1 (<i>DARC/ACKR1</i>) in Breast Tumors Is Associated with Survival, Circulating Chemokines, Tumor-Infiltrating Immune Cells, and African Ancestry

Abstract

Abstract Background: Tumor-specific immune response is an important aspect of disease prognosis and ultimately impacts treatment decisions for innovative immunotherapies. The atypical chemokine receptor 1 (ACKR1 or DARC) gene plays a pivotal role in immune regulation and harbors several single-nucleotide variants (SNV) that are specific to sub-Saharan African ancestry. Methods: Using computational The Cancer Genome Atlas (TCGA) analysis, case–control clinical cohort Luminex assays, and CIBERSORT deconvolution, we identified distinct immune cell profile–associated DARC/ACKR1 tumor expression and race with increased macrophage subtypes and regulatory T cells in DARC/ACKR1-high tumors. Results: In this study, we report the clinical relevance of DARC/ACKR1 tumor expression in breast cancer, in the context of a tumor immune response that may be associated with sub-Saharan African ancestry. Briefly, we found that for infiltrating carcinomas, African Americans have a higher proportion of DARC/ACKR1-negative tumors compared with white Americans, and DARC/ACKR1 tumor expression is correlated with proinflammatory chemokines, CCL2/MCP-1 (P &amp;lt;0.0001) and anticorrelated with CXCL8/IL8 (P &amp;lt;0.0001). Sub-Saharan African-specific DARC/ACKR1 alleles likely drive these correlations. Relapse-free survival (RFS) and overall survival (OS) were significantly longer in individuals with DARC/ACKR1-high tumors (P &amp;lt;1.0 × 10−16 and P &amp;lt;2.2 × 10−6, respectively) across all molecular tumor subtypes. Conclusions: DARC/AKCR1 regulates immune responses in tumors, and its expression is associated with sub-Saharan African-specific alleles. DARC/ACKR1-positive tumors will have a distinct immune response compared with DARC/AKCR1-negative tumors. Impact: This study has high relevance in cancer management, as we introduce a functional regulator of inflammatory chemokines that can determine an infiltrating tumor immune cell landscape that is distinct among patients of African ancestry.