Abstract C081: CD1d overexpression in triple negative breast cancer: A key factor of racial disparities in tumor progression and tumor microenvironment

Abstract Triple-negative breast cancer (TNBC) disproportionately affects African American (AA) patients, who face higher incidence and mortality compared to European American (EA) patients. The antigen-presenting molecule CD1d modulates immune responses via Natural Killer T (NKT) cells, but its role in TNBC disparities remains unclear. Using TCGA datasets, we found that high CD1d expression correlates with better overall survival in AA TNBC patients, contrasting with worse outcomes in low CD1d expressors, suggesting a race-specific role. We compared CD1d expression in EA-derived (MDA-MB-231) and AA-derived (MDA-MB-468) TNBC cell lines via western blot and flow cytometry, revealing higher CD1d (37 kDa) in EA cells compared to AA. Functional assays using CD1d modulators, zerumbone (20 μM, downregulates CD1d), α-GalCer (2 μM, upregulates CD1d), and Thymosin α1 (2 μM, upregulates CD1d) demonstrated CD1d’s direct role in tumor proliferation, colony formation, and spheroid growth. CD1d siRNA knockdown in both cell lines reduced these oncogenic phenotypes, confirming CD1d’s tumor-intrinsic effects. Intriguingly, CD1d expression on adipocytes (3T3-L1) modulated cytokine release, influencing TNBC cell growth when treated with conditioned media from Orlistat or α-GalCer-exposed adipocytes. These findings suggest that CD1d regulates tumor progression and adipocyte-mediated TME interactions differentially in AA vs. EA contexts. Higher CD1d in EA cells may enhance tumor proliferation, while in AA patients, CD1d may have more impact on immune modulatory role may paradoxically limit survival, potentially via the activation of immunosuppressive diverse NKT activation needs further studies. This study highlights CD1d as a novel therapeutic target to address TNBC disparities, necessitating further exploration of race-specific immunotherapy strategies to improve outcomes for AA patients. Citation Format: RITIS KUMAR SHYANTI, Rajesh Singh, MANOJ K MISHRA. CD1d overexpression in triple negative breast cancer: A key factor of racial disparities in tumor progression and tumor microenvironment [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 C081.