Abstract 5320: Integrative spatial omics reveals distinct tumor-promoting multicellular niches and immunosuppressive mechanisms in African American and European American patients with TNBC

Abstract Racial disparities in triple-negative breast cancer (TNBC) outcomes have been reported. However, the biological mechanisms underlying these disparities remain unclear. We integrated imaging mass cytometry and spatial transcriptomics, to characterize the tumor microenvironment (TME) of African American (AA) and European American (EA) patients with TNBC. The TME in AA patients was characterized by interactions between endothelial cells, macrophages, and mesenchymal-like cells, which were associated with poor patient survival. In contrast, the EA TNBC-associated niche is enriched in T-cells and neutrophils suggestive of an exhaustion and suppression of otherwise active T cell responses. Ligand-receptor and pathway analyses of race-associated niches found AA TNBC to be “immune cold” and hence immunotherapy resistant tumors, and EA TNBC as ‘inflamed’ tumors that evolved a distinctive immunosuppressive mechanism. Our study revealed the presence of racially distinct tumor-promoting and immunosuppressive microenvironments in AA and EA patients with TNBC, which may explain the poor clinical outcomes. Statement of Significance We have uncovered distinct tumor-promoting and immunosuppressive microenvironments that may contribute to the observed disparities in patient outcomes. Our findings lay the groundwork for developing race-specific therapeutic interventions, potentially improving outcomes for patients with TNBC. Given that chemotherapy and anti-PD1 therapy are currently available treatments for TNBC, our finding of race-specific spatial multicellular niche-associated cell-cell interactions suggest that these treatments may have racially distinct response profiles among TNBC patients. Hence, our novel insights on molecular and cellular interactions in TNBC stratified by race has the potential to inform personalized treatment strategies. Citation Format: Qian Zhu, Akhila Balasubramanian, Jaya Ruth Asirvatham, Badrajee Piyarathna, Jaspreet Kaur, Nada Mohamed, Ling Wu, Megha Chatterjee, Stacy Wang, Niloufar Pourfarrokh, Uttam Rasaily, Yitian Xu, Junjun Zheng, Deborah Jebakumar, Arundathi Rao, Shu-hsia Chen, Yi Li, Eric Chang, Xiaoxian Li, Ritu Aneja, Xiang H.-F. Zhang, Arun Sreekumar. Integrative spatial omics reveals distinct tumor-promoting multicellular niches and immunosuppressive mechanisms in African American and European American patients with TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5320.