Multi-organ landscape of terminal, therapy-resistant, cutaneous melanoma

Patients succumb to cutaneous melanoma (CM) after metastasis and failure of present-day MAPK inhibitor (MAPKi) and/or immune checkpoint blockade (ICB) therapies. Here we analyzed the genomic and transcriptomic landscape of multi-organ tumor and tumor-adjacent tissues from eleven rapid autopsies of individuals with CM who were treated with either or both MAPKi and/or ICB and succumbed to acquired therapy resistance. We discovered that, compared to melanoma from the preceding era, terminal, therapy-resistant melanoma harbor shifted mutational spectra and increased mutational burdens and frequencies in genes enriched for immune-evasive and resistance-driver processes. MAPKi specifically selects for signatures of defective homologous-recombination, mismatch, and base-excision repair mechanisms. Large, non-clustered deletions, inversions, and especially inter-chromosomal translocations dominate rearrangements, with breakpoints suggesting non-homologous end-joining. Organ-specific, tumor cel-enriched transcriptomes and ligand-receptor cross-talks (between tumors and tumor-adjacent macroenvironments) indicate differential interferon, neural, metabolic (oxidative-phosphorylation), and complement pathways. Terminal, therapy-resistant melanoma display an immune-desert, CD8+-macrophage-biased archetype enriched for T-cell exhaustion and type-2 immunity. Specifically, brain metastases enrich for pro-tumorigenic macrophages, mast cells, and eosinophils. This multi-organ perspective of lethal, therapy-resistant CM lays a foundation to improve therapeutic strategies.EGA study EGAS00001006644