Single-cell analysis reveals new evolutionary complexity in uveal melanoma

Nat Commun. 2020 Jan 24;11(1):496. doi: 10.1038/s41467-019-14256-1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cluster Analysis
  • DNA Copy Number Variations / genetics
  • Humans
  • Melanoma / genetics*
  • Melanoma / immunology
  • Melanoma / pathology
  • Neoplasm Metastasis
  • Sequence Analysis, RNA
  • Single-Cell Analysis*
  • Stochastic Processes
  • Transcription, Genetic
  • Tumor Microenvironment / immunology
  • Uveal Neoplasms / genetics*
  • Uveal Neoplasms / immunology
  • Uveal Neoplasms / pathology
  • V(D)J Recombination / genetics

Supplementary concepts

  • Uveal melanoma