Abstract C012: Atypical chemokine receptor 1 (ACKR1/DARC) is a biomarker of tumor immune response and prognosis in lung adenocarcinoma patients of African and European ancestry

Abstract Racial disparities in incidence, prognosis, and mortality rates exists between African-American (AA) and European-American (EA) lung adenocarcinoma (LUAD) patients in the United States. AAs experience an approximately 11% higher rate of LUAD diagnoses in which the incidence of LUAD is approximately 68.3 per capita for AA men and 61.5 per capita for EA men. Irrespective of smoking history, AA men and women experience notably poorer prognosis and significantly higher mortality rates relative to their EA counterparts, suggesting underlying biological influences. The exploitation of genetic variants unique to ancestral populations may proffer valuable insights for prognostic biomarkers that can improve risk-stratification and reduce LUAD mortality rates across diverse patient populations. The immune system plays a critical role in preventing tumor growth and progression and racial distinctions in immune response has been suggested to underlie disparities in LUAD incidence and mortality. Atypical chemokine receptor 1/Duffy antigen receptor for chemokines (ACKR1/DARC) is a decoy chemokine receptor expressed on erythrocytes, endothelial, and epithelial cells. ACKR1 internalizes and degrades pro-inflammatory chemokines to modulate the tumor immune microenvironment (TIME) and regulate leukocyte trafficking. The Duffy null allele, a variant in ACKR1, eliminates ACKR1 expression on erythrocytes and is linked to increased cancer susceptibility and progression. This allele occurs in 100% of West and Sub-Saharan African populations and in about 70% of AAs, suggesting its role in ancestry-related cancer disparities. In this study, we investigate how ACKR1 expression impacts prognosis and influence the tumor immune response in AA and EA LUAD patients. In TCGA, ACKR1 gene expression is markedly downregulated in LUAD tumors relative to matched normal tissue in all, EA, and AA patients (p0.05). Low ACKR1 gene expression correlated with poorer overall survival in all (p=0.039), EA (p=0.011), and AA (p=0.057) LUAD patients. CIBERSORT immune cell deconvolution revealed that ACKR1 gene expression positively correlates with CD8+ T cells, memory B cells, activated natural killer cells, and natural killer T cells and negatively correlates with myeloid-derived suppressor cells in LUAD tumors (p0.001). Collectively, our findings suggest ACKR1 may underlie a poorer immune response profile and prognosis observed in AA LUAD patients. Further elucidation of the influence of ACKR1 on the TIME in LUAD patients of distinct ancestral backgrounds may proffer insights into immunotherapeutic intervention. Citation Format: Benecia Jackson, Nikita Jinna, Loretta Erhunmwunsee Erhunmwunsee, Yate-Ching Yuan, Padmashree Rida. Atypical chemokine receptor 1 (ACKR1/DARC) is a biomarker of tumor immune response and prognosis in lung adenocarcinoma patients of African and European ancestry abstract. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C012.