What question did this study set out to answer?

To investigate the role of non-cell-autonomous mechanisms in early tumorigenesis in BRCA mutation carriers.

March 7, 2026

Abstract LB-A011: S100A9-releasing neutrophils promote breast cancer susceptibility in BRCA carriers

Puntos clave

To investigate the role of non-cell-autonomous mechanisms in early tumorigenesis in BRCA mutation carriers.
Analyzed human prophylactic mastectomy tissues using flow cytometry and spatial imaging.
Utilized BRCAmut mouse models and organoid cultures for mechanistic studies.
Conducted single-cell RNA sequencing and chromatin accessibility profiling.
Employed computational analyses for ligand-receptor inference and gene regulatory network reconstruction.
Examined neutrophil function through adoptive transfer and inhibition strategies.
BRCA deficiency activated an NF-κB-dependent chemokine program that recruits neutrophils to mammary glands before tumor development.
S100A9-positive neutrophils influenced luminal progenitors to adopt a basal-like identity, indicating early tumorigenic potential.
Identification of a neutrophil-dependent luminal progenitor subset crucial for cancer initiation mechanisms.
Blocking ALCAM receptor abolished neutrophil-induced transcriptional changes leading to cancer initiation.

Resumen

Abstract Women with germline BRCA1 or BRCA2 (BRCAmut) mutations face a markedly increased risk of breast cancer, yet irreversible prophylactic mastectomy remains the primary, effective preventive strategy. Current paradigms attribute tumour initiation to accumulation of secondary somatic mutations ('second hits'). Whether non-cell-autonomous mechanisms contribute to early oncogenic events in BRCA-mutated mammary tissue remains unexplored. We applied a multi-disciplinary experimental approach to characterise early tumorigenesis on the BRCA mutation background. Human prophylactic mastectomy tissues from BRCA mutation carriers and healthy donors were analysed using multiparametric flow cytometry and spatial imaging to define immune infiltration. To delve into the oncogenic mechanism, we combined transcriptomic, epigenomic, and functional perturbation approaches in mammary-restricted and whole-body BRCAmut mouse models and in luminal progenitor-derived organoid cultures. Single-cell RNA sequencing and single-nuclei ATAC (snRNAseq + snATACseq) data were integrated to reconstruct transcriptional and chromatin accessibility programs. Computational analyses included ligand-receptor inference, gene regulatory network reconstruction, transcription factor activity scoring, and pseudotime analysis to resolve lineage plasticity in epithelial cells under neutrophil exposure. Neutrophil function was interrogated through adoptive transfer, CXCR2 blockade, and immune compartment-restricted S100a9 depletion. BRCA deficiency induced an NF-κB-dependent chemokine program that recruited neutrophils to the mammary gland prior to oncogenesis. S100A9-positive neutrophils drove BRCAmut luminal progenitors (LASP) toward a basal-like fate. Single-nucleus ATAC and transcriptomic profiling identified a neutrophil-dependent LASP subset predisposed to a luminal-to-basal early tumorigenic switch, termed ‘Pre-tumoral LASP’, marked by genes linked to oncogenic reprogramming and present exclusively in neutrophil-treated glands. Pre-tumoral LASP displayed enrichment for NF-κB transcription factors, indicating NF-κB-driven transcriptional reprogramming. S100A9 was required for NF-κB activation and induction of the Pre-tumoral LASP state, and ALCAM was identified as the epithelial receptor for S100A9 in BRCA1mut cells. Importantly, blocking ALCAM abolished neutrophil-induced cancer-initiating programs and LASP trans-differentiation. These findings support a model in which neutrophil-secreted S100A9 binds ALCAM receptor on BRCA1mut luminal progenitors, triggering NF-κB activation and upregulation of a pre-tumoral transcriptional program which promotes the aberrant luminal-to-basal reprogramming upstream of oncogenesis. Citation Format: Boffa Letizia, Hannah F. Dewhurst, Camilla Paleari, Arianna Calcinotto. S100A9-releasing neutrophils promote breast cancer susceptibility in BRCA carriers abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr LB-A011.

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