Abstract B056: Tumor-associated ACKR1/DARC is correlated with a unique signature of proinflammatory chemokines and TILs in African-American women with breast cancer

Abstract

Abstract Part of the delicate interplay of interactions between tumor cells, immune cells, and other cell types cells contribute to the complexities of the tumor microenvironment (TME). Specific interactions between chemokines and their receptors can influence the migration of immune cells, thereby directing tumor immune responses. In general immune response, the Atypical Chemokine Receptor 1 (ACKR1/DARC) modulates chemokine levels through the sequestration of proinflammatory chemokines in circulation and transcytosis across endothelial and epithelial tissue. This can affect not only the concentration of immune cells brought to the TME, but also the profile of immune cell types, given that ACKR1 is a promiscuous binder of both chemokine classes (CXCL and CCL). ACKR1 also serves as an ancestral informative marker. The gene harbors a mutation (“Duffy-null”) in its promoter/5′ UTR region that abolishes its normal erythrocytic expression, a status that only exists in populations of sub-Saharan African descent, conferring an evolutionary advantage against malaria. This polymorphism is carried by 60-80% of African-Americans, and based on our findings, it can influence chemokine and immune cell migration in the context of tumorigenesis. Our study reveals the potential effect of this mutation in women with breast cancer (BC) by showing correlations between circulating chemokine concentrations, measured through Luminex multiplexing immunoassays, and relative levels of ACKR1 and tumor-infiltrating lymphocytes (TIL), scored through immunohistochemistry. Our initial investigation of epithelial expression of ACKR1 on breast tumors revealed supporting data of our hypothesis that differential expression of ACKR1 on breast tumor tissue is correlated with a distinct signature of TILs and associated proinflammatory chemokines. Specifically, lower levels of tumor-associated ACKR1 were seen in African-Americans, in addition to a less robust signature of TILs, including macrophages and T-cells. Genotyping for the Duffy-null mutation also showed correlations with proinflammatory chemokines, including CCL2 and CXCL8. Our data suggest that ACKR1 levels in circulation and tissues can indirectly influence the immune cell profile in African-American women with BC, potentially leading to changes in tumor aggressiveness and response to treatment. Citation Format: Brittany D. Jenkins, Talina Fleifel, Rachel N. Martini, Haythem Ali, Lisa A. Newman, Melissa B. Davis. Tumor-associated ACKR1/DARC is correlated with a unique signature of proinflammatory chemokines and TILs in African-American women with breast cancer [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B056.