Dissecting the treatment-naive ecosystem of human melanoma brain metastasis

Jana Biermann, Johannes C. Melms, Amit Dipak Amin, Yiping Wang, Lindsay A. Caprio, Alcida Karz, Somnath Tagore, Irving Barrera, Miguel A. Ibarra-Arellano, Massimo Andreatta, Benjamin T. Fullerton, Kristjan H. Gretarsson, Varun Sahu, Vaibhav S. Mangipudy, Trang T.T. Nguyen, Ajay Nair, Meri Rogava, Patricia Ho, Peter D. Koch, Matei BanuNelson Humala, Aayushi Mahajan, Zachary H. Walsh, Shivem B. Shah, Daniel H. Vaccaro, Blake Caldwell, Michael Mu, Florian Wünnemann, Margot Chazotte, Simon Berhe, Adrienne M. Luoma, Joseph Driver, Matthew Ingham, Shaheer A. Khan, Suthee Rapisuwon, Craig L. Slingluff, Thomas Eigentler, Martin Röcken, Richard Carvajal, Michael B. Atkins, Michael A. Davies, Albert Agustinus, Samuel F. Bakhoum, Elham Azizi, Markus Siegelin, Chao Lu, Santiago J. Carmona, Hanina Hibshoosh, Antoni Ribas, Peter Canoll, Jeffrey N. Bruce, Wenya Linda Bi, Praveen Agrawal, Denis Schapiro, Eva Hernando, Evan Z. Macosko, Fei Chen, Gary K. Schwartz, Benjamin Izar

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2591-2608.e30
JournalCell
Volume185
Issue number14
DOIs
StatePublished - Jul 7 2022

Keywords

  • brain metastasis
  • chromosomal instability
  • melanoma
  • neuronal-like cell state
  • single-cell genomics
  • spatial transcriptomics
  • tumor-microenvironment

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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