Purpose

Uveal Melanoma is a rare ocular malignancy; high-risk monosomy 3 tumors often show an increased density of tumor-infiltrating lymphocytes and macrophages. Histone deacetylases (HDACs) are a group of epigenetic modifiers, some of which are increased in monosomy 3 UM. We compared HDAC expression in Uveal Melanoma (UM) with the presence of infiltrating leukocytes. We furthermore determined whether expression was modifiable by interferon-gamma.

Methods

The expression of nine HDACs and CD3E, CD8 and CD68 leukocyte markers was determined using an Illumina HT12V4 array in 64 primary UM. In addition, HDAC and infiltrate data were obtained from the TCGA for 80 cases. Four UM cell lines were treated with two doses of IFNɤ (50 IU, 200 IU), for 48 hrs. Quantitative PCR (qPCR) was used for mRNA measurement of HDAC expression in-vitro.

Results

HDACs 1, 3, 7, and 8 were positively associated with CD3E, CD8A and CD68 leukocyte markers (P ≤ 0.05). Analysis from the TCGA similarly showed that HDACs 1, 3, and 8 were positively correlated with the presence of CD3E and CD8A.

When looking at the possible effect of IFNɤ on four UM cell lines (OMM1, OMM2.5, MP38 and Mp46) we found that (in contrast to HLA-A and HLA-B mRNA expression which was induced in all four cell lines), HDACs 1, 4, 5, 7, and 8 were induced in two out of four UM cell lines (OMM2.5 and MP38).

Conclusions

As HDACs were previously shown to be upregulated in high-risk monosomy 3 UM tumors, we wondered whether they are associated with the presence of tumor-infiltrated lymphocytes and macrophages. Our findings indicate that several HDACs show positive correlation with tumor-infiltrating lymphocytes and macrophages. As these HDACs were sensitive to induction, there may be a role for the infiltrating leukocytes in the upregulation of HDACs in Uveal melanoma.