Spatial characterization of macrophage-enriched tumor regions in triple-negative breast cancer

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Abstract
BACKGROUND: The spatial organization of immune cells within tumors is an important area of investigation in studies of interactions between tumor cells and the tumor microenvironment. This is particularly relevant because some immune cells function through direct contact with their target cells, whereas others communicate over a distance via paracrine signaling involving cytokines. Thus, the topography of tumor cells and microenvironmental cells may determine the possibility and nature of intercellular interactions and thereby influence the functional effects of immune cells. AIM: This study aimed to compare the spatial transcriptomic profiles of tumor and stromal regions enriched in macrophages in triple-negative breast cancer. METHODS: Eight patients with triple-negative breast cancer were included. Spatial transcriptomic analysis was performed on formalin-fixed, paraffin-embedded tissue sections using high-throughput RNA sequencing with the 10X Visium platform. The annotated spots enriched in intraepithelial and stromal macrophages were used for downstream bioinformatic analysis. RESULTS: A total of 437 differentially expressed genes were identified between the two groups of spots containing macrophages with distinct spatial localization. Spots with intraepithelial macrophages were characterized by activation of processes related to cytokine and chemokine signaling, regulation of regulatory T-cell differentiation, organization of cell–cell contacts, wound healing, and inhibition of viral activity. Spots enriched in stromal macrophages demonstrated activation of biological processes associated with the regulation of angiogenesis, cell migration and recruitment, cell adhesion, and stromal remodeling. CONCLUSION: Macrophage topography within primary tumors of triple-negative breast cancer is associated with their functional characteristics. These fundamental findings may be useful for developing prognostic criteria and therapeutic approaches aimed at modulating the tumor microenvironment to improve long-term outcomes in patients with triple-negative breast cancer.

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