LAG3 and Its Ligands Show Increased Expression in High-Risk Uveal Melanoma

Abstract

Uveal melanoma (UM) is a rare ocular malignancy which originates in the uveal tract, and often gives rise to metastases. Potential targets for immune checkpoint inhibition are lymphocyte-activation gene 3 (LAG3) and its ligands. We set out to analyse the distribution of these molecules in UM. The expression of mRNA was determined using an Illumina array in 64 primary UM from Leiden. The T lymphocyte fraction was determined by digital droplet PCR. In a second cohort of 15 cases from Leiden, mRNA expression was studied by Fluidigm qPCR, while a third cohort consisted of 80 UM from TCGA. In the first Leiden cohort, <i>LAG3</i> expression was associated with the presence of epithelioid cells (<i>p</i> = 0.002), monosomy of chromosome 3 (<i>p</i> = 0.004), and loss of BAP1 staining (<i>p</i> = 0.001). In this Leiden cohort as well as in the TCGA cohort, <i>LAG3</i> expression correlated positively with the expression of its ligands: <i>LSECtin</i>, <i>Galectin-3</i>, and the HLA class II molecules <i>HLA-DR</i>, <i>HLA-DQ</i>, and <i>HLA-DP</i> (all <i>p</i> < 0.001). Furthermore, ligands <i>Galectin-3</i> and <i>HLA class II</i> were increased in monosomy 3 tumours and the expression of <i>LAG3</i> correlated with the presence of an inflammatory phenotype (T cell fraction, macrophages, <i>HLA-A</i> and <i>HLA-B</i> expression: all <i>p</i> < 0.001). High expression levels of <i>LAG3</i> (<i>p</i> = 0.01), <i>Galectin-3</i> (<i>p</i> = 0.001), <i>HLA-DRA1</i> (<i>p</i> = 0.002), <i>HLA-DQA1</i> (<i>p</i> = 0.04), <i>HLA-DQB2</i> (<i>p</i> = 0.03), and <i>HLA-DPA1</i> (<i>p</i> = 0.007) were associated with bad survival. We conclude that expression of the LAG ligands <i>Galectin-3</i> and <i>HLA class II</i> strongly correlates with <i>LAG3</i> expression and all are increased in UM with Monosomy 3/BAP1 loss. The distribution suggests a potential benefit of monoclonal antibodies against LAG3 or Galectin-3 as adjuvant treatment in patients with high-risk UM.