Single-cell analysis reveals new evolutionary complexity in uveal melanoma

Uveal melanoma (UM) is a highly metastatic cancer that, in contrast to cutaneous melanoma, is largely unresponsive to checkpoint immunotherapy. In this study we interrogate the tumour microenvironment at single-cell resolution using scRNA-seq of 59,915 tumour and non-neoplastic cells from 8 primary and 3 metastatic samples. A subset analysis of tumour cells confirms the global genomic landscape established from bulk analysis and reveals newly described subclonal genomic complexity and transcriptional states consistent with phenotype plasticity. The immune compartment comprises a previously unrecognized diversity of cell types, including CD8+ T cells expressing the checkpoint marker LAG3, as opposed to PD1 or CTLA4. We identified clonally expanded plasma cells in a rare metastasis from an indolent slow-growing class 1B tumour indicating a role for of antibody-mediated immunity. These findings reveal a dynamic ecosystem in which UM demonstrates new evolutionary complexity. LAG3 is identified as a potential candidate for immune checkpoint blockade in high risk UM. We performed single-cell RNAseq of primary and metastatic human uveal melanoma to profile the tumor microenvironment and indentify subclonal tumor architecture. Single cell 3' and 5' RNAseq data of primary and metastatic human uveal melanoma was performed using the 10X Genomics Chromium platform and sequenced on Illumina Nextseq500. RNA-Seq raw data is to be made available through dbGaP (controlled access) due to patient privacy concerns: https://www.ncbi.nlm.nih.gov/gap/?term=phs001861.v1.p1