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Tina Jehs, Helene Juel, Carsten Faber, Inge Bronkhorst, Martine Jager, Mogens Nissen; Inflammatory stress upregulates chemokine gene expression in uveal melanoma cell lines resulting in increased monocyte chemotaxis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):172.
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© ARVO (1962-2015); The Authors (2016-present)
Uveal melanoma is the most common primary intraocular tumor in adults. In contrast with many other malignancies, the presence of infiltrating T cells and macrophages is associated with a poor prognosis. Moreover, higher concentrations of several inflammatory cytokines and chemokines in the vitreous fluid correlate with an increasing tumor size underlying the significance of inflammation in the uveal melanoma pathogenesis. The purpose of this study is to investigate in vitro the effect of activated T cells on uveal melanoma cell gene expression and ability to attract monocytes.
T cells were purified from healthy human donors, activated with anti- CD3/CD28 beads and co-cultured over three uveal melanoma cell lines (92.1, Mel 270 and Mel 290) for 64h in a membrane insert. Supernatant was collected and RNA was purified from the uveal melanoma cell lines and gene expression analysis was performed with whole-transcriptome microarrays. For the migration assay, CD14+ monocytes purified from healthy human donors were added in the upper chamber of a transwell plate. Supernatants were added to the lower chamber and plates were incubated for 2.5h. The number of migrated cells was counted with flow cytometry.
Gene expression analysis of uveal melanoma cell lines co-cultured with activated T cells resulted in a more than two-fold upregulation of over 500 genes including several genes coding for chemokines and cytokines such as CCL2, CXCL8, CXCL9, CXCL10, CXCL11, IL6, IL1α and IL1β. This increase coincides with increased monocyte attraction towards co-culture supernatants in a migration assay.
Cytokines derived from activated T cells shift the uveal melanoma cell-transcriptome towards a more inflammatory state, including the upregulation of several cytokines and chemokines, which lead to an increased migration of monocytes. Therefore, uveal melanoma cells might actively participate in generating an inflammatory environment around the tumor which corresponds to a worse prognosis. With these findings immunotherapy may prove to be a useful strategy in treating uveal melanoma.
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