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

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. ### Competing Interest Statement JRA served as an advisor for Roche. Xiaoxian Li has served as an advisor for Astra Zeneca, Roche, Eli Lilly, and Onviv, and Champions Oncology has funded research in Xiaoxian Li lab. Dr. Sreekumar reports grants from the Agilent Foundation, non-financial support from Sri Sathya Sai Institute for Higher Learning, India, and personal fees from Karkinos Health Care Pvt. Ltd., India, outside the submitted work.