Dissecting the treatment-naive ecosystem of human melanoma brain metastasis

• DOI: 10.1016/j.cell.2022.06.007
• Publication Date: 2022-07-07T14:42:30Z
• Authors: Jana Biermann; Johannes C. Melms; Amit Dipak Amin; Yiping Wang; Lindsay A. Caprio; Alcida Karz; Somnath Tagore; Irving Barrera; Miguel A. Ibarra-...; Massimo Andreatta; Benjamin T. Fulle...; Kristjan H. Greta...; Varun Sahu; Vaibhav S. Mangipudy; Trang T.T. Nguyen; Ajay Nair; Meri Rogava; Patricia Ho; Peter D. Koch; Matei Banu; Nelson Humala; Aayushi Mahajan; Zachary H. Walsh; Shivem B. Shah; Daniel H. Vaccaro; Blake Caldwell; Michael Mu; Florian Wünnemann; Margot Chazotte; Simon Berhe; Adrienne M. Luoma; Joseph Driver; Matthew Ingham; Shaheer A. Khan; Suthee Rapisuwon; Craig L. Slingluff; Thomas Eigentler; Martin Röcken; Richard Carvajal; Michael B. Atkins; Michael A. Davies; Albert Agustinus; Samuel F. Bakhoum; Elham Azizi; Markus Siegelin; Chao Lu; Santiago J. Carmona; Hanina Hibshoosh; Antoni Ribas; Peter Canoll; Jeffrey N. Bruce; Wenya Linda Bi; Praveen Agrawal; Denis Schapiro; Eva Hernando; Evan Z. Macosko; Fei Chen; Gary K. Schwartz; Benjamin Izar
• Keywords: 0303 health sciences; chromosomal instability; single-cell genomics; spatial transcriptomics; Brain Neoplasms; Neurosciences; tumor-microenvironment; Biological Sciences; CD8-Positive T-Lymphocytes; Medical and Health Sciences; neuronal-like cell state; 03 medical and health sciences; melanoma; 2.1 Biological and endogenous factors; Humans; brain metastasis; RNA-Seq; Aetiology; Melanoma; Ecosystem; Cancer; Biotechnology; Developmental Biology

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.