Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.
Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.
- 2022
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.
English
0092-8674
10.1016/j.cell.2022.06.007 [doi] NIHMS1819979 [mid] PMC9677434 [pmc] S0092-8674(22)00712-7 [pii]
*Brain Neoplasms
*Melanoma
Brain Neoplasms/dt [Drug Therapy]
Brain Neoplasms/sc [Secondary]
CD8-Positive T-Lymphocytes/pa [Pathology]
Ecosystem
Humans
RNA-Seq
Washington Cancer Institute
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
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.
English
0092-8674
10.1016/j.cell.2022.06.007 [doi] NIHMS1819979 [mid] PMC9677434 [pmc] S0092-8674(22)00712-7 [pii]
*Brain Neoplasms
*Melanoma
Brain Neoplasms/dt [Drug Therapy]
Brain Neoplasms/sc [Secondary]
CD8-Positive T-Lymphocytes/pa [Pathology]
Ecosystem
Humans
RNA-Seq
Washington Cancer Institute
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't