Increase in HLA-G1 proteolytic shedding by tumor cells: a regulatory pathway controlled by NF-κB inducers

HLA-G is expressed by tumors, in which it contributes to the evasion of immunosurveillance. NF- Kappa B appears to be a candidate for regulating HLA-G expression, since it is considered to be a hallmark of cancer. We investigated the role of NF- Kappa B in modulating HLA-G expression in HLA-G-positive tumor cells, JEG-3 (chorio-carcinoma), FON (melanoma), and M8-HLA-Gl (HLA-Gl-transfected melanoma). The treatment of tumor cells with two NF- Kappa B inducers, tumor necrosis factor- alpha and phorbol 12-myristate 13-acetate, decreased HLA-G1 cell surface expression but increased intracytoplasmic HLA-G proteins. Reduction in HLA-G1 cell surface expression is driven by NF- Kappa B and involves a proteolytic shedding process dependent on metalloproteinase activity. In contrast, an increase in intracytoplasmic HLA-G proteins involves post-transcriptional mechanisms that are independent of NF- Kappa B. These results, and the fact that soluble HLA-G1 reduces the cytotoxicity of the NKL cell line, lead us to propose a novel regulatory pathway for HLA-G expression by tumor cells that may have particular relevance in tumor escape.