Single-cell analysis reveals new evolutionary complexity in uveal melanoma

Michael A. Durante, Daniel A. Rodriguez, Stefan Kurtenbach, Jeffim N. Kuznetsov, Margaret I. Sanchez, Christina L. Decatur, Helen Snyder, Lynn G. Feun, Alan S. Livingstone, J. William Harbour

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Uveal melanoma (UM) is a highly metastatic cancer that, in contrast to cutaneous melanoma, is largely unresponsive to checkpoint immunotherapy. Here, we interrogate the tumor microenvironment at single-cell resolution using scRNA-seq of 59,915 tumor and non-neoplastic cells from 8 primary and 3 metastatic samples. Tumor cells reveal novel subclonal genomic complexity and transcriptional states. Tumor-infiltrating immune cells comprise a previously unrecognized diversity of cell types, including CD8+ T cells predominantly expressing the checkpoint marker LAG3, rather than PD1 or CTLA4. V(D)J analysis shows clonally expanded T cells, indicating that they are capable of mounting an immune response. An indolent liver metastasis from a class 1B UM is infiltrated with clonally expanded plasma cells, indicative of antibody-mediated immunity. This complex ecosystem of tumor and immune cells provides new insights into UM biology, and LAG3 is identified as a potential candidate for immune checkpoint blockade in patients with high risk UM.

Original languageEnglish (US)
Article number496
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Durante, M. A., Rodriguez, D. A., Kurtenbach, S., Kuznetsov, J. N., Sanchez, M. I., Decatur, C. L., Snyder, H., Feun, L. G., Livingstone, A. S., & Harbour, J. W. (2020). Single-cell analysis reveals new evolutionary complexity in uveal melanoma. Nature communications, 11(1), [496]. https://doi.org/10.1038/s41467-019-14256-1