Atypical chemokine receptor 1 (DARC/ACKR1) in breast tumors is associated with survival, circulating chemokines, tumor-infiltrating immune cells, and African ancestry

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