Transforming growth factor-beta down-regulates major histocompatibility complex class I antigen expression and increases the susceptibility of uveal melanoma cells to natural killer cell-mediated cytolysis.

摘要

Intraocular melanomas, especially those of the anterior segment, reside within an immunologically privileged milieu. Aqueous humour contains a variety of immunomodulatory factors that are believed to contribute to ocular immune privilege. Among these is transforming growth factor-beta (TGF-beta), which has been shown to down-regulate major histocompatibility complex (MHC) class I antigens on normal cells. Since the susceptibility of tumour cells to natural killer (NK) cell-mediated lysis is inversely correlated with the expression of MHC class I antigens, tumour cells exposed to TGF-beta might be expected to experience enhanced susceptibility to NK-mediated killing. This was examined by incubating two human uveal melanoma cell lines in the presence of TGF-beta and evaluating the expression of MHC class I antigen and susceptibility to NK cell-mediated lysis. OCM1 and OCM8 melanoma cells constitutively express high levels of class I antigen (85-90% positive) and low susceptibility to NK-mediated lysis in vitro (3-8%). Incubation with TGF-beta produced a significant reduction in class I antigen expression (52-62%) and a proportional increased susceptibility to NK cell-mediated cytolysis (17%). Analogous effects were found using a human uveal melanoma cell line (OCM3) that constitutively expresses low amounts of class I (< 5% positive) and high NK susceptibility (35% lysis). Stimulation of class I antigen expression by incubation with interferon-gamma resulted in a sharp increase in class I expression (80% positive) and a comparable diminution in susceptibility to NK cell-mediated lysis (< 10%). The results indicate that TGF-beta, at concentrations found in the aqueous humour, can significantly alter MHC class I antigen expression and the susceptibility of ocular melanoma cells to NK cell-mediated cytolysis.