Melanoma brain metastases (MBM) are common in patients with advanced melanoma, but the underlying biology is poorly understood. To address this gap, Biermann and Melms et al. compared multi-modal single cell transcriptomics of 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs; MBM and ECM were from different patients), coupled with functional validation in human and mouse models. MBM cells adopted a neuronal-like phenotype associated with increased chromosomal instability, and contained increased numbers of pro-tumorigenic macrophages and dysfunctional TOX+CD8+ T cells compared with ECMs.
Contributed by Katherine Turner
ABSTRACT: Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX(+)CD8(+) T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.