Human Uveal Melanoma Cells Produce Macrophage Migration-Inhibitory Factor to Prevent Lysis by NK Cells

Abstract

Human uveal melanoma arises in an immune privileged ocular environment in which both adaptive and innate immune effector mechanisms are suppressed. Uveal melanoma is the most common intraocular tumor in adults and is derived from tissues in the eye that produce macrophage migration-inhibitory factor (MIF), a cytokine that has recently been demonstrated to produce immediate inhibition of NK cell-mediated lytic activity. Although NK cell-mediated lysis of uveal melanomas is inhibited in the eye, melanoma cells that disseminate from the eye are at risk for surveillance by NK cells. Moreover, uveal melanoma cells demonstrate a propensity to metastasize to the liver, an organ with one of the highest levels of NK activity in the body. Therefore, we speculated that uveal melanomas produced MIF as a means of escaping NK cell-mediated lysis. Accordingly, seven primary uveal melanoma cell lines and two cell lines derived from uveal melanoma metastases were examined for their production of MIF. MIF was detected in melanoma culture supernatants by both ELISA and the classical bioassay of macrophage migration inhibition. Melanoma-derived MIF inhibited NK cell-mediated lysis of YAC-1 and uveal melanoma cells. Cell lines derived from uveal melanoma metastases produced approximately twice as much biologically active MIF as cultures from primary uveal melanomas. Inhibition of NK cell-mediated killing by uveal melanoma-derived MIF was specifically inhibited in a dose-dependent manner by anti-MIF Ab. The results suggest that human uveal melanoma cells maintain a microenvironment of immune privilege by secreting active MIF that protects against NK cell-mediated killing.

Modulation of the Tumor Cell Phenotype by IFN-γ Results in Resistance of Uveal Melanoma Cells to Granule-Mediated Lysis by Cytotoxic Lymphocytes

“…3). NK cell-mediated killing of UM lines has been previously shown to be inhibited by factors secreted from tumor cells (30). However, conditioned culture supernatants of UM lines did not affect the viability or cytotoxic activity of the effectors used in our study (data not shown), consistent with the results of the cold target inhibition assays.…”

Release of Macrophage Migration Inhibitory Factor and CXCL8/Interleukin-8 from Lung Epithelial Cells Rendered Necrotic by Influenza A Virus Infection

“…Both cell lines are also characterized by higher basal MIF levels than normal cells. This phenomenon of enhanced MIF expression in tumor cells has recently been described in a series of studies and has been correlated with MIF's property of promoting tumor progression and angiogenesis (10,20,30,33).…”

NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo

“…Haplotypes and clinical features of the patients are reported in Table 1. The primary human uveal melanoma cell lines OM431 (34) and OCM1 (35); the liver metastatic human uveal melanoma cell lines OMM1 (36) and OMM2.3 (37); and the B6-derived murine melanoma cell lines B16, B16F0, B16F10 and the MT/ret melanoma cells, a kind gift of A. Prevost-Blondel (Institut Cochin, Paris, France) (24) were all cultured in RPMI 1640 medium/5% FCS/2 mM l-glutamine/50 μM 2-mercaptoethanol in a 5% CO2 humidified atmosphere at 37°C. All tumor cells were used for assays within 1 hour of collection, and viability was always greater than 95% as determined by Trypan blue exclusion.…”