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W. Yang, P. W. Chen, H. Li, H. Alizadeh, J. Y. Niederkorn; PD-L1 Expression by Human Uveal Melanoma Inhibits T-Cell Function. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2398.
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Tumors employ a variety of strategies to evade immune surveillance. The costimulatory molecule PD-L1 which binds to its receptor PD-1 expressed on T-cells plays an inhibitory role in the regulation of T cell activation and function. The purpose of this study is to test the hypothesis that PD-L1 expression by uveal melanoma promotes tumor immune escape from T cell-mediated killing by inhibiting T cell function.
A panel of primary and metastatic uveal melanoma cell lines was evaluated for PD-L1 expression by RT-PCR and FACS analysis respectively. Uveal melanoma-bearing eyes were detected for PD-L1 expression in situ by immunohistochemistry. PD-L1 function was tested by co-culturing IFN-γ -pretreated uveal melanoma cells with activated Jurkat T cells for 48 hours and assessing IL-2 production of T cell by ELISA.
Six primary uveal melanoma cell lines and two metastases cell lines constitutively expressed PD-L1 mRNA, while five of the nine primary and one of the five metastatic uveal melanoma cell lines tested constitutively expressed PD-L1 protein at various levels, which indicates a posttranscriptional control of PD-L1 surface expression. However, all primary and metastatic uveal melanoma cell lines upregulated PD-L1 expression significantly after stimulation with IFN-γ (P<0.01). Immunhistochemistry demonstrated that PD-L1 was not expressed by uveal melanoma in situ. IL-2 production by activated Jurkat cells was decreased significantly when the cells co-cultured with IFN-γ pretreated uveal melanoma cells (P<0.01). IL-2 production was restored to over 70% by addition of anti-PD-L1 or anti- PD-1 antibody into the co-culture assays (P<0.01).
Expression of PD-L1 by uveal melanoma cells regulates T cell function by suppressing IL-2 production. This study implies that the presence of IFN-γ in the tumor local microenvironment promotes upregulation of PD-L1 expression by uveal melanoma, which may, in part, promote immune escape by impairing T cell function. The selective blockade of PD-L1 is a potential strategy in T cell-based immunotherapy of uveal melanomas.
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