Abstract Chronic psychosocial stress contributes to cancer progression by altering immune function through neuroendocrine and inflammatory pathways. African American (AA) populations, disproportionately affected by systemic stressors such as racism and socioeconomic disadvantage, exhibit elevated inflammatory profiles and cancer disparities. The Duffy Antigen Receptor for Chemokines (DARC/ACKR1) plays a key role in immune regulation through sequestration of pro-inflammatory chemokines. However, individuals with Duffy-null status, common among those of African descent, lack this regulatory mechanism on red blood cells, influencing circulating inflammatory profiles. While higher DARC expression within breast tumors has been linked to improved survival, the joint influence of psychosocial stress and Duffy-null status on immune response and cancer outcomes remains unclear. To investigate these relationships, we are conducting a retrospective analysis using data from the NCI Maryland Breast Cancer Stress Study, which includes 121 breast cancer patients aged 28–90 years (mean = 56.3, SD = 12.6), 46.3% of whom identified as African American and 53.7% as European American (EA). Perceived stress was measured using the 10-item Cohen Perceived Stress Scale (PSS). Systemic inflammatory profiles were determined using the Olink multiplex assay, measuring 92 inflammatory markers in patient sera. In a separate subset of the cohort, we performed an immunohistochemical expression analysis of immuno-oncological markers within tumor specimens stratified by Duffy status. Duffy-null status was determined through single-plex single nucleotide variant genotyping (rs2814778). Preliminary observations indicate that AA participants in our study disproportionately resided in neighborhoods with higher deprivation, with a mean neighborhood deprivation index (NDI) of 2.28 (SD = 2.30), when compared to −0.22 (SD = 2.01) for EA participants. While average PSS scores did not differ significantly between AA and EA patients, additional differences in environmental exposure due to neighborhood structural disadvantage may also impact biological stress pathways in these patients. We therefore hypothesize that among AA patients, Duffy-null individuals exposed to both high perceived stress and neighborhood deprivation will exhibit the most elevated levels of pro-inflammatory cytokines and chemokines. This hypothesis is currently being tested. Here, multivariable linear regression and cox proportional hazards models will be employed to evaluate associations between perceived stress, Duffy-null status, the neighborhood deprivation index (NDI), PSS, and inflammatory markers, and survival. We expect Duffy-null individuals exposed to high neighborhood deprivation and high stress to have the greatest inflammatory burden and poorest survival outcomes. In conclusion, this study will offer novel insight into how psychosocial stress and genetic variation may interact to influence immune regulation and cancer outcomes in racially diverse populations. Citation Format: Jamirah Y. Chevrin, Rachel Martini, Tiffany H. Dorsey, Stefan Ambs, Melissa B. Davis. The DARC side of stress: The role of DARC-mediated chemokine regulation in stress-driven inflammation and breast cancer disparities 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 A114.
Chevrin et al. (2025) studied this question.