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

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.