Abstract 4886: An in-depth single-cell map of inflammatory breast cancer reveals wide-scaled restructuring associated to an immunosuppressive and inflammation-like microenvironment

Abstract Inflammatory Breast Cancer (IBC) has increasingly been recognised as a distinct form of breast cancer, that is characterised by its distinctive clinical presentation, as well as its fast onset and poor prognosis. Despite previous efforts, the underlying molecular heterogeneity of IBC remains poorly understood. We used single-cell transcriptomics to dissect the transcriptional landscape of IBC at single-cell resolution, and elucidate differences to non-inflammatory breast cancer (non-IBC), of which we created and curated a subtype-matched comparison dataset. Our analysis revealed a previously underappreciated role of the microenvironment in driving the immune suppressive and angiogenic phenotype of IBC. Furthermore, we identified key transcriptional signatures associated with IBC aggressiveness, including dysregulated pathways across all major cell compartments. Within each compartment, we used a combination of approaches to assign functional roles to subsets of cells, including expression of marker genes, gene programmes and projection onto thoroughly annotated reference-spaces. We thus identify cell populations present in significantly different proportions between IBC and non-IBC. Interestingly, among the populations enriched in IBC we identified iCAFs, pro-inflammatory M1-like myeloid cells as well as regulatory T cells. In non-IBC on the other hand, enriched cell types include myCAFs, M2-like myeloid cells and cytotoxic T cells. In addition to differences in the cell composition, we also find differences in the expression of certain markers and gene programmes. A pseudo-time analysis of T cells reveals a shift towards an exhausted T cell phenotype in IBC, in line with a lower expression of HLA genes in its epithelial compartment. In agreement with the known angiogenic phenotype, we also see an enrichment in mitogenic signatures in IBC-associated endothelial cells. In summary, our data describe an immunosuppressive environment, highlighted by the presence of cell types with an inflammation-like phenotype, signs of immune evasion and exhaustion and angiogenesis. Our comprehensive and unique single-cell transcriptomic dataset of this rare form of breast cancer provides valuable insights into the complex cellular composition of IBC, offering a foundation for further functional exploration of involved pathways, and finally development of new targeted therapy approaches. Our study contributes to a deeper understanding of IBC biology and pathology, enabling future identification of direly needed biomarkers and therapeutic approaches for this hard-to-treat breast cancer type. Citation Format: Paul Schwerd-Kleine, Tasneem Cheytan, Roberto Würth, Ewgenija Gutjahr, Laura Michel, Verena Thewes, Peter Lichter, Andreas Schneeweiss, Andreas Trumpp, Martin Sprick. An in-depth single-cell map of inflammatory breast cancer reveals wide-scaled restructuring associated to an immunosuppressive and inflammation-like microenvironment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4886.