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Cancer Epidemiol Biomarkers Prev. 2019 Apr;28(4):690-700. doi: 10.1158/1055-9965.EPI-18-0955.

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

Author information

1
Department of Genetics, Franklin College of Arts and Sciences, University of Georgia, Athens, Georgia.
2
Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia.
3
University Cancer and Blood Center, Athens, Georgia.
4
Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, Alabama.
5
Department of Population Sciences, City of Hope Comprehensive Cancer Center, Duarte, California.
6
Department of Pathology, Henry Ford Health System, Detroit, Michigan.
7
Department of Hematology and Oncology, Henry Ford Health System, Detroit, Michigan.
8
Department of Surgery, Henry Ford Health System, Detroit, Michigan.
9
Department of Molecular Biology and Biochemistry, Augusta University/University of Georgia Medical Partnership, Athens, Georgia.
10
Department of Genetics, Franklin College of Arts and Sciences, University of Georgia, Athens, Georgia. mbd4001@med.cornell.edu.
11
Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan.

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 <0.0001) and anticorrelated with CXCL8/IL8 (P <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 <1.0 × 10-16 and P <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.

PMID:
30944146
PMCID:
PMC6450416
[Available on 2020-04-01]
DOI:
10.1158/1055-9965.EPI-18-0955

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