Lag3 and its ligands show increased expression in high-risk uveal melanoma

Zahra Souri, Annemijn P.A. Wierenga, Wilma G.M. Kroes, Pieter A. van der Velden, Robert M. Verdijk, Michael Eikmans, Gregorius P.M. Luyten, Martine J. Jager*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)
18 Downloads (Pure)

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, LAG3 expression was associated with the presence of epithelioid cells (p = 0.002), monosomy of chromosome 3 (p = 0.004), and loss of BAP1 staining (p = 0.001). In this Leiden cohort as well as in the TCGA cohort, LAG3 expression correlated positively with the expression of its ligands: LSECtin, Galectin-3, and the HLA class II molecules HLA-DR, HLA-DQ, and HLA-DP (all p < 0.001). Furthermore, ligands Galectin-3 and HLA class II were increased in monosomy 3 tumours and the expression of LAG3 correlated with the presence of an inflammatory phenotype (T cell fraction, macrophages, HLA-A and HLA-B expression: all p < 0.001). High expression levels of LAG3 (p = 0.01), Galectin-3 (p = 0.001), HLA-DRA1 (p = 0.002), HLA-DQA1 (p = 0.04), HLA-DQB2 (p = 0.03), and HLA-DPA1 (p = 0.007) were associated with bad survival. We conclude that expression of the LAG ligands Galectin-3 and HLA class II strongly correlates with LAG3 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.

Original languageEnglish
Article number4445
JournalCancers
Volume13
Issue number17
DOIs
Publication statusPublished - 3 Sep 2021

Bibliographical note

Funding Information:
This research was funded by a grant to Z.S. from The Iranian Ministry of Science Research and Technology, Grant UL 2011-4991 from the Dutch Cancer Society (KWF), Stichting Leids Oogheelkundig Ondersteunings Fonds LOOF and a Horizon 2020 grant from the European Commu-nity, CURE UM, nr. 667787.

Funding Information:
Funding: This research was funded by a grant to Z.S. from The Iranian Ministry of Science Research and Technology, Grant UL 2011-4991 from the Dutch Cancer Society (KWF), Stichting Leids Oogheelkundig Ondersteunings Fonds LOOF and a Horizon 2020 grant from the European Community, CURE UM, nr. 667787.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Fingerprint

Dive into the research topics of 'Lag3 and its ligands show increased expression in high-risk uveal melanoma'. Together they form a unique fingerprint.

Cite this