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Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.

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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: 2022 ISSN:

0092-8674

Name of journal: CellAbstract: 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.All authors: Agrawal P, Agustinus A, Amin AD, Andreatta M, Atkins MB, Azizi E, Bakhoum SF, Banu M, Barrera I, Berhe S, Bi WL, Biermann J, Bruce JN, Caldwell B, Canoll P, Caprio LA, Carmona SJ, Carvajal R, Chazotte M, Chen F, Davies MA, Driver J, Eigentler T, Fullerton BT, Gretarsson KH, Hernando E, Hibshoosh H, Ho P, Humala N, Ibarra-Arellano MA, Ingham M, Izar B, Karz A, Khan SA, Koch PD, Lu C, Luoma AM, Macosko EZ, Mahajan A, Mangipudy VS, Melms JC, Mu M, Nair A, Nguyen TTT, Rapisuwon S, Ribas A, Rocken M, Rogava M, Sahu V, Schapiro D, Schwartz GK, Shah SB, Siegelin M, Slingluff CL Jr, Tagore S, Vaccaro DH, Walsh ZH, Wang Y, Wunnemann FFiscal year: FY2023 Digital Object Identifier:

https://dx.doi.org/10.1016/j.cell.2022.06.007

Date added to catalog: 2022-12-13

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Item type	Current library	Collection	Call number	Status	Date due	Barcode
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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