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Dissecting the treatment-naive ecosystem of human melanoma brain metastasis
- Biermann, Jana;
- Melms, Johannes C;
- Amin, Amit Dipak;
- Wang, Yiping;
- Caprio, Lindsay A;
- Karz, Alcida;
- Tagore, Somnath;
- Barrera, Irving;
- Ibarra-Arellano, Miguel A;
- Andreatta, Massimo;
- Fullerton, Benjamin T;
- Gretarsson, Kristjan H;
- Sahu, Varun;
- Mangipudy, Vaibhav S;
- Nguyen, Trang TT;
- Nair, Ajay;
- Rogava, Meri;
- Ho, Patricia;
- Koch, Peter D;
- Banu, Matei;
- Humala, Nelson;
- Mahajan, Aayushi;
- Walsh, Zachary H;
- Shah, Shivem B;
- Vaccaro, Daniel H;
- Caldwell, Blake;
- Mu, Michael;
- Wünnemann, Florian;
- Chazotte, Margot;
- Berhe, Simon;
- Luoma, Adrienne M;
- Driver, Joseph;
- Ingham, Matthew;
- Khan, Shaheer A;
- Rapisuwon, Suthee;
- Slingluff, Craig L;
- Eigentler, Thomas;
- Röcken, Martin;
- Carvajal, Richard;
- Atkins, Michael B;
- Davies, Michael A;
- Agustinus, Albert;
- Bakhoum, Samuel F;
- Azizi, Elham;
- Siegelin, Markus;
- Lu, Chao;
- Carmona, Santiago J;
- Hibshoosh, Hanina;
- Ribas, Antoni;
- Canoll, Peter;
- Bruce, Jeffrey N;
- Bi, Wenya Linda;
- Agrawal, Praveen;
- Schapiro, Denis;
- Hernando, Eva;
- Macosko, Evan Z;
- Chen, Fei;
- Schwartz, Gary K;
- Izar, Benjamin
- et al.
Published Web Location
https://doi.org/10.1016/j.cell.2022.06.007Abstract
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.
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