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
Author(s)
Biermann J., Melms J.C., Amin A.D., Wang Y., Caprio L.A., Karz A., Tagore S., Barrera I., Ibarra-Arellano M.A., Andreatta M., Fullerton B.T., Gretarsson K.H., Sahu V., Mangipudy V.S., Nguyen TTT, Nair A., Rogava M., Ho P., Koch P.D., Banu M., Humala N., Mahajan A., Walsh Z.H., Shah S.B., Vaccaro D.H., Caldwell B., Mu M., Wünnemann F., Chazotte M., Berhe S., Luoma A.M., Driver J., Ingham M., Khan S.A., Rapisuwon S., Slingluff C.L., Eigentler T., Röcken M., Carvajal R., Atkins M.B., Davies M.A., Agustinus A., Bakhoum S.F., Azizi E., Siegelin M., Lu C., Carmona S.J., Hibshoosh H., Ribas A., Canoll P., Bruce J.N., Bi W.L., Agrawal P., Schapiro D., Hernando E., Macosko E.Z., Chen F., Schwartz G.K., Izar B.
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
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
Create date
19/07/2022 10:10
Last modification date
22/07/2022 6:38
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