Dissecting the treatment-naive ecosystem of human melanoma brain metastasis

Jana Biermann1, Johannes C Melms2, Amit Dipak Amin2, Yiping Wang1, Lindsay A Caprio2, Alcida Karz3, Somnath Tagore4, Irving Barrera5, Miguel A Ibarra-Arellano6, Massimo Andreatta7, Benjamin T Fullerton8, Kristjan H Gretarsson9, Varun Sahu9, Vaibhav S Mangipudy9, Trang T T Nguyen10, Ajay Nair8, Meri Rogava2, Patricia Ho2, Peter D Koch11, Matei Banu12, Nelson Humala12, Aayushi Mahajan12, Zachary H Walsh11, Shivem B Shah11, Daniel H Vaccaro11, Blake Caldwell11, Michael Mu11, Florian Wünnemann6, Margot Chazotte6, Simon Berhe8, Adrienne M Luoma13, Joseph Driver14, Matthew Ingham8, Shaheer A Khan8, Suthee Rapisuwon15, Craig L Slingluff Jr16, Thomas Eigentler17, Martin Röcken18, Richard Carvajal8, Michael B Atkins19, Michael A Davies20, Albert Agustinus21, Samuel F Bakhoum22, Elham Azizi23, Markus Siegelin10, Chao Lu9, Santiago J Carmona7, Hanina Hibshoosh10, Antoni Ribas24, Peter Canoll10, Jeffrey N Bruce12, Wenya Linda Bi25, Praveen Agrawal26, Denis Schapiro27, Eva Hernando3, Evan Z Macosko28, Fei Chen29, Gary K Schwartz8, Benjamin Izar30

  1. Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Program for Mathematical Genomics, Columbia University, New York, NY 10032, USA.
  2. Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  3. Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA.
  4. Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  5. Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  6. Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, 69120 Heidelberg, Germany.
  7. Department of Oncology UNIL CHUV, Lausanne Branch, Ludwig Institute for Cancer Research Lausanne, CHUV and University of Lausanne, Lausanne, 1066 Épalinges, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
  8. Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
  9. Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
  10. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
  11. Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
  12. Department of Neurological Surgery, New York Presbyterian/Columbia University Irving Medical Center, New York, NY 10032, USA.
  13. Department of Cancer Immunology and Virology, Dana-Farber Cancer Center, Boston, MA 02215, USA.
  14. Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  15. Division of Hematology/Oncology, Medstar Washington Cancer Institute, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
  16. Department of Surgery, University of Virginia, Charlottesville, VA, USA.
  17. Department of Dermatology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Dermatology, Venereology and Allergology, 10117, Berlin, Germany.
  18. Department of Dermatology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
  19. Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
  20. Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA.
  21. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pharmacology, Weill Cornell Graduate School, New York, NY 10065, USA.
  22. Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  23. Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA; Irving Institute for Cancer Dynamics, Columbia University, New York, NY 10027, USA.
  24. Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA), Los Angeles, CA 90024, USA.
  25. Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  26. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA.
  27. Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, 69120 Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
  28. Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA.
  29. Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  30. Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Program for Mathematical Genomics, Columbia University, New York, NY 10032, USA; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: bi2175@cumc.columbia.edu.

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+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.

Presented By Johannes C Melms

Cancer BiologyNicholas Liao2022-07 (Jul)