Expression and regulation of non-classical HLA-G in renal cell carcinoma.

Under physiological conditions, the non-classical major histocompatibility complex class Ib molecule human leukocyte antigen G (HLA-G) is selectively expressed in placental trophoblasts, thymus and cornea. In pathological situations, HLA-G expression was frequently found in tumour cells of distinct origin, thereby allowing these tumour cells to escape immune surveillance. Although HLA-G expression occurs at a relatively high frequency in renal cell carcinoma (RCC) of the clear cell subtype, the molecular mechanisms of its aberrant expression in RCC has not yet been determined. Therefore, the constitutive and cytokine-mediated HLA-G expression as well as its mode of regulation was investigated. In addition to HLA-G-specific mRNA expression, membrane-bound and soluble/shed HLA-G protein was determined. Eight of 14 RCC cell lines analysed (57%) exhibited HLA-G-specific transcripts, whereas only 6 of 14 RCC cell lines (43%) expressed HLA-G protein, suggesting a post-transcriptional control of HLA-G in some cases. Treatment of RCC cell lines with either interferon-gamma or interleukin-10, respectively, increased HLA-G-specific mRNA and protein in six of eight HLA-G(+) RCC lines (75%), but not in HLA-G(-) RCC cells. A 5'-aza-2-deoxycytidine (5-Aza-dC)-mediated demethylation of the HLA-G promoter DNA resulted in an enhanced HLA-G expression in four of six RCC cell lines, whereas a de novo induction of HLA-G was only observed in one HLA-G(-) RCC cell line on treatment with 5-Aza-dC. Thus, there exist multiple mechanisms controlling HLA-G expression in RCC, which might also have an impact on the development of RCC-specific immunotherapies.