TY - JOUR
T1 - Atypical chemokine receptor 1 (DARC/ACKR1) in breast tumors is associated with survival, circulating chemokines, tumor-infiltrating immune cells, and African ancestry
AU - Jenkins, Brittany D.
AU - Martini, Rachel N.
AU - Hire, Rupali
AU - Brown, Andrea
AU - Bennett, Briana
AU - Brown, I'nasia
AU - Howerth, Elizabeth W.
AU - Egan, Mary
AU - Hodgson, Jamie
AU - Yates, Clayton
AU - Kittles, Rick
AU - Chitale, Dhananjay
AU - Ali, Haythem
AU - Nathanson, David
AU - Nikolinakos, Petros
AU - Newman, Lisa
AU - Monteil, Michele
AU - Davis, Melissa B.
N1 - Funding Information:
We are eternally grateful for the donors and volunteers who have supported our research efforts through participation and donating their blood or tissue for use as cohort samples. These brave women include the participants of the "Be the Research" program at UGA, TCGA patients, Komen Biospecimen Tissue Bank, and the Henry Ford International Breast Registry. B.D. Jenkins is a Howard Hughes Medical Institute Gilliam Fellow. Special thanks to Ben Rybicki and Nancy Manley for helpful discussions on data interpretations, and study scope and impact. This work was supported by grants: R21-CA210237-03 (NIH/NCI; to M.B. Davis), U54-MD007585-26 (NIH/RCMI; to C. Yates), U54 CA118623 (NIH/NCI; to C. Yates), (NIH/ NCI) 1 R21 CA188799-01 (to C. Yates), and SAC160072 (Komen; to L. Newman).
Publisher Copyright:
©2019 American Association for Cancer Research.
PY - 2019/4
Y1 - 2019/4
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85063898786&partnerID=8YFLogxK
U2 - 10.1158/1055-9965.EPI-18-0955
DO - 10.1158/1055-9965.EPI-18-0955
M3 - Article
C2 - 30944146
AN - SCOPUS:85063898786
SN - 1055-9965
VL - 28
SP - 690
EP - 700
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
IS - 4
ER -