Considering the well established role of nonclassical HLA-G class I molecules in inhibiting natural killer (NK) cell function, the consequence of abnormal HLA-G expression in malignant cells should be the escape of tumors from immunosurveillance. To examine this hypothesis, we analyzed HLA-G expression and NK sensitivity in human malignant melanoma cells. Our analysis of three melanoma cell lines andex vivobiopsy demonstrated that (i) IGR and M74 human melanoma cell lines exhibit a high level of HLA-G transcription with differential HLA-G isoform transcription and protein expression patterns, (ii) a higher level of HLA-G transcriptionex vivois detected in a skin melanoma metastasis biopsy compared with a healthy skin fragment from the same individual, and (iii) HLA-G protein isoforms other than membrane-bound HLA-G1 protect IGR from NK lysis. It thus appears of critical importance to consider the specific role of HLA-G expression in tumors in the design of future cancer immunotherapies.

HLA-G plays an essential role in feto-maternal tolerance by inhibiting lysis by maternal NK cells. The factors that allow tissue-specific activation of HLA-G gene expression in trophoblasts remain to be characterized. We investigated the potential effect of IL-10, a cytokine which is secreted in placenta, on HLA-G gene transcription in trophoblasts. Using Northern blot, RNase protection assay and RT-PCR analysis, we demonstrated that IL-10 enhances steady-state levels of HLA-G transcription in cultured trophoblast cells. We further tested the effect of IL-10 on HLA-G gene transcription and protein expression in peripheral blood monocytes, showing that IL-10 can up-regulate HLA-G cell surface expression in this cell type. This effect of IL-10 is selective, since classical MHC class I products and MHC class II are down-regulated in monocytes following IL-10 treatment. Induction of HLA-G expression by IL-10 on monocytes may thus play a role in down-regulation of the immune response. We propose that IL-10 secretion by trophoblasts during pregnancy may also influence the HLA class I expression pattern at the feto-maternal barrier, thus protecting the fetus from rejection. This should be taken into consideration in the design of treatment for pathologies of pregnancy.

The HLA-G gene displays several peculiarities that are distinct from those of classical HLA class I genes. The unique structure of the HLA-G molecule permits a restricted peptide presentation and allows the modulation of the cells of the immune system. Although polymorphic sites may potentially influence all biological functions of HLA-G, those present at the promoter and 3′ untranslated regions have been particularly studied in experimental and pathological conditions. The relatively low polymorphism observed in the MHC-G coding region both in humans and apes may represent a strong selective pressure for invariance, whereas, in regulatory regions several lines of evidence support the role of balancing selection. Since HLA-G has immunomodulatory properties, the understanding of gene regulation and the role of polymorphic sites on gene function may permit an individualized approach for the future use of HLA-G for therapeutic purposes.