Abstract C088: DARC/ACKR1 expression modulates immune regulation and influences tumor progression in triple-negative breast cancer
Authors: Guerra Yanira , Martini Rachel , Ginter Paula , Stonaker Brian , Gyan Kofi , Bensenhaver Jessica , Chen Yalei , Krei Ishmael , Aitpillah Frances S , Adinku Michael O , Oppong Joseph K , Adjei Ernest K , Baffour Awuah , Ankomah Kwasi , Osei-Bonsu Ernest B , Jabril Aisha , Bekele Mahteme , Abebe Engida , Yates Clayton , Newman Lisa , Elemento Olivier , Davis Melissa B 
Published: September 2024

Abstract
African American women have been observed to have higher rates of Triple-Negative Breast Cancer (TNBC) diagnosis, earlier age of onset, and higher mortality rates from TNBC compared to European American women. Recent studies have shown that TNBC tumors exhibit increased immunogenicity. This heightened immune cell infiltration is associated with better prognosis and outcomes. The Duffy Antigen Receptor for Chemokines (DARC/ACKR1) has been proposed as a driver of immune regulation within breast cancer. The association of DARC/ACKR1 with African ancestry stems from evolutionary pressures against malaria. A single nucleotide variant, named the Duffy-null allele, results in the loss of DARC/ACKR1 on red blood cells and subsequently lends immunity from Plasmodium vivax malaria. While this variant change provides protection against malaria, it also may have significant implications for immune regulation and inflammation. The DARC/ACKR1 protein is also expressed on breast tumor epithelial cells, with gene expression showing considerable variation across breast tumors. Past work has shown a strong positive correlation between DARC/ACKR1 expression and the abundance of total tumor-associated leukocytes (TAL) across all breast cancer subtypes. This correlation supports the hypothesis that DARC/ACKR1 expression significantly influences the immune cell landscapes within the tumor microenvironment (TME). To further characterize the role of DARC/ACKR1 in the TNBC TME, we performed imaging mass cytometry (IMC) on an African-enriched cohort of primary TNBC tumor sections, using a 36-antibody panel to identify tumor, stromal, and immune cell populations. After image acquisition, we ran cell segmentation, quantified the signals of the 36 markers per cell, conducted cell phenotyping to identify specific cell populations, and performed downstream data visualization in R and JMP. DARC/ACKR1 status was determined via immunohistochemistry-based methods and verified via pathology review. We report that positive DARC/ACKR1 invasive carcinoma interpretation correlates with an increase in the immune cell proportion as compared to patients with negative DARC/ACKR1 interpretation. This indicates that the presence of DARC/ACKR1 appears to foster an immune-supportive environment within tumors. Interestingly though, we also observed an increasing trend of M2 macrophages, which have been linked to cancer growth and invasion, among patients with DARC/ACKR1-positive tumors. The implications of these findings are significant for understanding tumor progression and developing new treatment strategies. Differences in immune cell landscapes between DARC/ACKR1-positive and DARC/ACKR1-negative tumors may dictate tumor behavior and responsiveness to therapy, highlighting the potential of DARC/ACKR1 as a biomarker. This work underscores the need for further investigation into the role of DARC/ACKR1 in chronic inflammation and its impact on the TME, potentially paving the way for novel therapeutic options aimed at improving outcomes for women of African Ancestry with TNBC.
Citation Format: Yanira Guerra, Rachel Martini, Paula Ginter, Brian Stonaker, Kofi Gyan, Jessica Bensenhaver, Yalei Chen, Ishmael Krei, Frances S Aitpillah, Michael O Adinku, Joseph K Oppong, Ernest K Adjei, Awuah Baffour, Kwasi Ankomah, Ernest B Osei-Bonsu, Aisha Jabril, Mahteme Bekele, Engida Abebe, Clayton Yates, Lisa Newman, Olivier Elemento, Melissa B Davis. DARC/ACKR1 expression modulates immune regulation and influences tumor progression in triple-negative breast cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C088.