Immunogenomics and spatial proteomic mapping highlight distinct neuro-immune architectures in melanoma vs. non-melanoma-derived brain metastasis

Abstract Background Brain metastases (BrMs) are a devastating complication of solid tumours. A better understanding of BrMs biology is needed to address their challenging clinical management. Methods Immunogenomic and digital spatial analyses were applied to interrogate the peripheral blood and tumour specimens derived from 53 unique patients with BrMs originating from different solid tumours. Results At craniotomy time, patients with melanoma-derived brain metastasis (MBM) displayed in the periphery lower neutrophil–lymphocyte ratio (NLR) compared to non-melanoma-derived brain metastasis (non-MBM). Regardless of the primary tumour source, higher NLR was associated with reduced overall survival (OS). Tumour MicroEnviroment genomic evaluations revealed higher expression of genes identifying NK, CD8 and B cells in MBM vs. non-MBM. Moreover, MBM patients with longer OS displayed increased CD8+ cell infiltration. Spatial proteomic analysis further highlighted enriched infiltration of CD8+ cells, antigen-presenting cells, T-cell agonists and B cells in MBM. Conversely, increased expression of genes and proteins associated with neurodevelopment, cell–cell adhesion and neutrophil infiltration were observed in non-MBM. Conclusions These findings reveal an increased immunogenicity of MBM vs non-MBM and highlight the presence of a unique neuro-immune interplays in MBM vs non-MBM, suggesting that a balance between neuro-immune architectures might be associated with diverging clinical outcome of patients with BrMs.