Multi-omic profiling reveals discrepant immunogenic properties and a unique tumor microenvironment among melanoma brain metastases

Gino K. In, Jennifer R. Ribeiro, Jun Yin, Joanne Xiu, Matias A. Bustos, Fumito Ito, Frances Chow, Gabriel Zada, Lindsay Hwang, April K.S. Salama, Soo J. Park, Justin C. Moser, Sourat Darabi, Evidio Domingo-Musibay, Maria L. Ascierto, Kim Margolin, Jose Lutzky, Geoffrey T. Gibney, Michael B. Atkins, Benjamin IzarDave S.B. Hoon, Ari M. VanderWalde

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1 Scopus citations

Abstract

Melanoma brain metastases (MBM) are clinically challenging to treat and exhibit variable responses to immune checkpoint therapies. Prior research suggests that MBM exhibit poor tumor immune responses and are enriched in oxidative phosphorylation. Here, we report results from a multi-omic analysis of a large, real-world melanoma cohort. MBM exhibited lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM), which was independent of tumor mutational burden. Among MBM, there were fewer computationally inferred immune cell infiltrates, which correlated with lower TNF and IL12B mRNA levels. Ingenuity pathway analysis (IPA) revealed suppression of inflammatory responses and dendritic cell maturation pathways. MBM also demonstrated a higher frequency of pathogenic PTEN mutations and angiogenic signaling. Oxidative phosphorylation (OXPHOS) was enriched in MBM and negatively correlated with NK cell and B cell-associated transcriptomic signatures. Modulating metabolic or angiogenic pathways in MBM may improve responses to immunotherapy in this difficult-to-treat patient subset.

Original languageEnglish (US)
Article number120
Journalnpj Precision Oncology
Volume7
Issue number1
DOIs
StatePublished - Dec 2023

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© 2023, The Author(s).

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