Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases [Research Articles]

There is a critical need to improve our understanding of the pathogenesis of melanoma brain metastases (MBMs). Thus, we performed RNA-sequencing (RNA-seq) on 88 resected MBMs and 42 patient-matched extracranial metastases (ECMs); tumors with sufficient tissue also underwent whole exome sequencing, T cell receptor sequencing, and immunohistochemistry. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival. Comparison to patient-matched ECMs identified significant immunosuppression and enrichment of oxidative phosphorylation (OXPHOS) in MBMs. Gene expression analysis of intracranial and subcutaneous xenografts, and a spontaneous MBM model, confirmed increased OXPHOS gene expression in MBMs, which was also detected by direct metabolite profiling and [U-13C]-glucose tracing in vivo. IACS-010759, an OXPHOS inhibitor currently in early-phase clinical trials, improved survival of mice bearing MAPKi-resistant intracranial melanoma xenografts and inhibited MBM formation in the spontaneous MBM model. The results provide new insights into the pathogenesis and therapeutic resistance of MBMs.

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