Association of tumor Schwann cells with epithelial-mesenchymal transition and immune-suppressive microenvironment in triple-negative breast cancer

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PURPOSE: Tumor-associated nerves have recently emerged as an understudied key regulator of cancer biology. However, its quantification using histological or transcriptomic approaches is challenging because their small diameters hinder reliable detection and their cell bodies that hold most mRNA reside outside the tumor. This study evaluated a Schwann cell (SC)-related transcriptomic score as a surrogate for tumor-associated nerves in tumors from triple-negative breast cancer (TNBC) patients. METHODS: Transcriptomic and clinical data from three independent TNBC cohorts, TCGA (n = 170), METABRIC (n = 335), and SCAN-B (n = 174) were analyzed. An SC score was calculated from SC-related gene signatures, and spatial transcriptomics was used to validate SC localization. In addition, seven independent neoadjuvant chemotherapy (NAC) cohorts were analyzed to evaluate the association between SC score and treatment response. Associations between the SC score and clinical features, genomic features, proliferation, treatment response, and the tumor microenvironment (TME) were evaluated. RESULTS: SC signature genes spatially localized to intratumoral nerve regions, confirming that the SC score reflects their presence within tumors. SC-high tumors were associated with lower mutation burden and with less cell proliferation in the TCGA, METABRIC, and SCAN-B cohorts. SC-high tumors were also associated with low immune activity and fewer infiltrating immune cells, along with enrichment of epithelial-mesenchymal transition (EMT), TGF-beta signaling and stromal remodeling pathways. CONCLUSIONS: The SC score-high TNBC is associated with lower cell proliferation, enhanced stromal remodeling and EMT and suppressed immune activity, suggesting a role of neural-associated TME features in shaping TNBC biology.

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