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Zahra Souri, Gre Luyten, Martine J Jager; Expression of immune checkpoint LAG3 is associated with high risk uveal melanoma. Invest. Ophthalmol. Vis. Sci. 2021;62(8):37.
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Uveal melanoma is a rare malignancy of the eye originating from the uveal tract. While treatment with immune checkpoint inhibitors such as anti-PD1 is often effective in the treatment of cutaneous melanoma metastases, no effective treatment for UM metastases has as yet been developed. A potential new target for immune checkpoint inhibitors is Lymphocyte-activation gene 3 (LAG3). LAG3 is an immune inhibitory receptor which is expressed on T cells and shows a great affinity for MHC Class II. Another ligand of LAG3 is Galectin-3. As LAG3 is known as an indicator of T cell exhaustion in tumors, we set out to investigate which Uveal Melanoma express this immune checkpoint and its ligands, MHC Class II and Galectin-3, in order to get a better insight in possible immunotherapeutic approaches.
The mRNA expression of LAG3, MHC II, Galectin-3, PD1, markers of tumor-infiltrating lymphocytes (TIL) and tumor-associated macrophages (TAM) was determined using an Illumina HT12V4 array in 64 primary UM. In order to confirm our analysis, the mRNA expression of the same markers was studied using 80 UM samples from the TCGA cohort.
When comparing the level of LAG3 expression with clinic-pathological characteristics in the Leiden set of 64 tumors, a higher expression was associated with the presence of epithelioid cells (P= 0.05), ciliary body involvement (P= 0.05) and loss of BAP1 staining (P= 0.001); the level of LAG3 expression was significantly higher in monosomy 3 tumors compared to disomy 3 (P= 0.004). Furthermore, LAG3 showed a positive correlation with TILs and TAMs (CD3, CD4, CD8, CD68, all P<0.001). LAG3 expression correlated positively with expression of HLA-DP (P< 0.001), HLA-DQ (P< 0.001), two probes for HLA-DR (P< 0.001; P< 0.001), Galectin3 (P< 0.001) and PD1 (P< 0.001).When looking at the TCGA data, similarly, LAG3 (P< 0.001), HLA-DP (P= 0.001), HLA-DQ (P< 0.001), HLA-DR (P= 0.001), and Galectin3 (P< 0.001) were significantly higher in M3 compared to D3 UM tumors.
We show that LAG3 is highly expressed in M3 UM tumors; LAG3 is strongly associated with expression of its ligand MHC Class II, and with the presence of TILs and TAMs. We suggest that LAG3 might have a potential role for the exhaustion of T cells present in the UM tumor environment and propose that due to its association with high risk tumor characteristics, LAG3 may be a good target for immunotherapy in UM.
This is a 2021 ARVO Annual Meeting abstract.
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