Souri Zahra, Wierenga Annemijn P A, Kroes Wilma G M, van der Velden Pieter A, Verdijk Robert M, Eikmans Michael, Luyten Gregorius P M, Jager Martine J
Department of Ophthalmology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Cancers (Basel). 2021 Sep 3;13(17):4445. doi: 10.3390/cancers13174445.
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, expression was associated with the presence of epithelioid cells ( = 0.002), monosomy of chromosome 3 ( = 0.004), and loss of BAP1 staining ( = 0.001). In this Leiden cohort as well as in the TCGA cohort, expression correlated positively with the expression of its ligands: , , and the HLA class II molecules , , and (all < 0.001). Furthermore, ligands and were increased in monosomy 3 tumours and the expression of correlated with the presence of an inflammatory phenotype (T cell fraction, macrophages, and expression: all < 0.001). High expression levels of ( = 0.01), ( = 0.001), ( = 0.002), ( = 0.04), ( = 0.03), and ( = 0.007) were associated with bad survival. We conclude that expression of the LAG ligands and strongly correlates with 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.
葡萄膜黑色素瘤（UM）是一种起源于葡萄膜的罕见眼部恶性肿瘤，常发生转移。免疫检查点抑制的潜在靶点是淋巴细胞激活基因3（LAG3）及其配体。我们着手分析这些分子在UM中的分布情况。使用Illumina阵列测定了来自莱顿的64例原发性UM中mRNA的表达。通过数字液滴PCR测定T淋巴细胞分数。在来自莱顿的15例病例的第二个队列中，通过Fluidigm qPCR研究mRNA表达，而第三个队列由来自TCGA的80例UM组成。在第一个莱顿队列中，表达与上皮样细胞的存在（P = 0.002）、3号染色体单体性（P = 0.004）和BAP1染色缺失（P = 0.001）相关。在这个莱顿队列以及TCGA队列中，表达与其配体的表达呈正相关：CD74、MHC II类分子HLA-DRA、HLA-DRB1和HLA-DQB1（均P < 0.001）。此外，配体CD74和LGALS3在3号染色体单体性肿瘤中增加，且LGALS3的表达与炎症表型的存在相关（T细胞分数、巨噬细胞、CXCL9和CXCL10表达：均P < 0.001）。LAG3（P = 0.01）、LGALS3（P = 0.001）、HLA-DRA（P = 0.002）、HLA-DRB1（P = 0.04）、HLA-DQB1（P = 0.03）和CD74（P = 0.007）的高表达水平与不良生存相关。我们得出结论，LAG配体LGALS3和CD74的表达与LAG3表达密切相关，且在伴有3号染色体单体性/BAP1缺失的UM中均增加。这种分布表明，针对LAG3或半乳糖凝集素-3的单克隆抗体作为高危UM患者的辅助治疗可能有益。
