Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.
Citation: Cell. 185(14):2591-2608.e30, 2022 07 07.PMID: 35803246Institution: Washington Cancer InstituteForm of publication: Journal ArticleMedline article type(s): Journal Article | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov'tSubject headings: *Brain Neoplasms | *Melanoma | Brain Neoplasms/dt [Drug Therapy] | Brain Neoplasms/sc [Secondary] | CD8-Positive T-Lymphocytes/pa [Pathology] | Ecosystem | Humans | RNA-SeqYear: 2022ISSN:- 0092-8674
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Journal Article | MedStar Authors Catalog | Article | 35803246 | Available | 35803246 |
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. Copyright © 2022 Elsevier Inc. All rights reserved.
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