Abstract
Purpose:
Programmed cell death-1/ ligand (PD1/PDL1) is a pathway that negatively regulates T-cell activity. A targeted therapy blocking PD1/PDL1 has shown unprecedented tumor response in metastatic cancers. PDL1 expression in tumors has been associated with therapy response; however, this association is controversial due to the lack of a validated commercially available antibody. Despite advances in uveal melanoma (UM) treatment, 40% of patients will develop metastases from which 90% will die. The aim of this study was to analyze PDL1 expression and its prognostic value in UM.
Methods:
Placenta sections and 92.1 UM cells were used as a positive control to validate a newly PDL1 antibody (E1L3N clone). Negative controls were established by silencing the PDL1 gene with siRNA in UM cell lines. After validation, 40 eyes with UM and clinical information were analyzed. The retinal pigmented epithelium present in each case was used as an internal positive control. Immunohistochemical expression of PDL1 was scored based on extent:(0-3) and intensity (1= less than internal control; 2= higher or equal to internal control). A final score(IRS)was obtained multiplying both values. Low expression was considered an IRS 0-3 and high 4-6. Chi-square, and survival analysis using log-rank test were used to determine statistical significance.
Results:
Placenta showed staining limited to the trophoblast. UM 92.1 cells showed positive PDL1 staining. After gene silencing, there was a 9-fold decrease in PDL1 mRNA, which corresponded with a significant decrease in IRS (P<0.0001). In UM samples, 4 cases were excluded due to absence of staining in the inner positive controls. PDL1 expression was seen in 88.6% of the cases, with 38.9% of cases showing high expression. Lower PDL1 IRS was observed in epithelioid cells compared to spindle and mixed cell type (P=0.03). No differences were seen in tumor size, vascular loops, lymphocytic infiltration, and metastases.
Conclusions:
The commercially available anti PDL1 monoclonal antibody (E1L3N) shows high specificity. To the best of our knowledge, this is the first report showing positivity for PDL1 in UM cases. In our series, PDL1 is expressed in most cases. These results support the evaluation of anti-PD/PDL1 therapy in UM. Further studied are needed to determine the importance of this marker for predicting response to treatments targeting this pathway.