Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.
Details
Serval ID
serval:BIB_10AEEAB455A8
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.
Journal
Cell
ISSN
1097-4172 (Electronic)
ISSN-L
0092-8674
Publication state
Published
Issued date
07/07/2022
Peer-reviewed
Oui
Volume
185
Number
14
Pages
2591-2608.e30
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
Publication Status: ppublish
Publication Status: ppublish
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 <sup>+</sup> CD8 <sup>+</sup> 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.
Keywords
Brain Neoplasms/drug therapy, Brain Neoplasms/secondary, CD8-Positive T-Lymphocytes/pathology, Ecosystem, Humans, Melanoma, RNA-Seq, brain metastasis, chromosomal instability, melanoma, neuronal-like cell state, single-cell genomics, spatial transcriptomics, tumor-microenvironment
Pubmed
Web of science
Create date
19/07/2022 9:10
Last modification date
30/03/2023 5:53