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Y. He, E.S. Mayhew, J.A. Mellon, J.Y. Niederkorn; Expression and Function of IL-2 and IL-15 Receptors on Human Uveal Melanoma Cells . Invest. Ophthalmol. Vis. Sci. 2003;44(13):764.
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Purpose: The presence of either tumor-infiltrating lymphocytes (TIL), or tumor-infiltrating macrophages (TIM) has been correlated with a poor prognosis in uveal melanoma patients. One potential explanation for this paradox is the possibility that TIL and TIM secrete growth factors that promote the survival of melanoma cells in situ. Since interleukin-2 and interleukin-15 receptors (IL-2R & IL-15R) have been detected on some murine neoplasms, we examined the expression of these receptors on some human uveal melanoma cell lines, the effect of exogenous IL-2 and IL-15 on melanoma cell proliferation, and the effect of IL-2 and IL-15 on the susceptibility of melanoma cells to NK cell-mediated cytolysis. Methods: Nine human uveal melanoma cell lines, including two cell lines from uveal melanoma metastases were tested by flow cytometry for the expression of human IL-2R (CD25) or IL-15R alpha. Melanoma cells were cultured in the presence of various concentrations of recombinant human IL-2 (100, 500, and 1,000 u/ml) or IL-15 (1, 5 and 10 ng/ml) for 24, 48, and 72 hr. Cell proliferation was determined by tritiated thymidine uptake and receptor expression was assessed by flow cytometry. Standard NK-cell mediated cytolysis was carried out by conventional 4 hr 51Cr-release assay. Effect of IL-15 on tumor cell apoptosis induced either by anti-Fas or TRAIL were evaluated on three uveal melanoma cell lines, in which percent apoptosis was detected by annexin V assay. Results: All of the uveal melanoma and metastasis cell lines tested demonstrated at least some level of IL-2R and IL-15R expression that was above the negative control cells (Chang human liver cell line). In seven of the nine uveal melanoma cell lines and in both of the metastasis cell lines, IL-2 induced a 3 to 8 fold upregulation of IL-2R expression (P<0.05) compared to untreated controls. Although IL-2 did not affect the proliferation of six of the nine uveal melanoma cell lines, it did induce a 32-57% increase in the proliferation of the two metastatic cell lines. IL-15 induced proliferation on all tested cell lines (4-68% increase above the controls) in a dose-independent pattern. Both IL-2 and IL-15 reduced sensitivities of tested tumor cells to NK cell-mediated cytolysis. No significant effect was observed on either FasL-mediated or TRAIL-induced tumor cell apoptosis. Conclusion: The results suggest that secretion of IL-2 by TIL and IL-15 by TIM might affect the malignant behavior of human uveal melanomas by stimulating the proliferation of subpopulations of metastatic cells within the primary neoplasm and reducing their susceptibility to NK cell-mediated cytolysis.
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