HLA-G in Melanoma: A New Strategy to Escape from Immunosurveillance?

Abstract

The non-classical HLA class-I molecule HLA-G, primarily expressed on fetal cells of the human placenta, has been shown to play a crucial role in maintaining an immuno-privileged environment at the materno-fetal interface. Fetal trophoblast cells are protected from attack by CD8+ cytotoxic T lymphocytes due to their lacking expression of classical HLA class-I molecules, again rendering them susceptible to natural killer (NK) cell lysis. HLA-G has been shown to interact with killing inhibitory receptors, hereby rescuing the fetal placenta cells from NK cell attack. Likewise, classical HLA class-I molecules are known to be frequently downregulated or lost during the development of malignancies. This abnormality is often associated with a poor clinical course of disease, despite of the frequent detection of tumor-infiltrating NK cells. This controversy seemed to be resolved with the detection of HLA-G expression on cells of malignant melanoma and other solid tumors. Since interferon(IFN)s are known for their ability of upregulation or induction of HLA-G expression, the potential function of HLA-G as a new strategy of cancer cells to escape from immunosurveillance might be of particular importance in malignant melanoma. The frequent use of IFN-α in the immunotherapy of this malignancy might possibly worsen the already impaired antitumoral immune response state of melanoma patients. However, several studies recently failed to detect any HLA-G protein expression in cancer cell lines and tissues of different origin, particularly in malignant melanoma, yet rendering the expression and function of HLA-G in malignancies as a possibly overrated matter of controversial debate.

Reinstalling Antitumor Immunity by Inhibiting Tumor-Derived Immunosuppressive Molecule IDO through RNA Interference

“…Immunosuppression and evasion can be achieved through a variety of mechanisms, many of which are well-characterized, experimentally supported, and at the disposal of cancer cells. These include secretion of Th2-associated cytokines such as IL-10 or TGF-ß leading to Th2 polarization (17,(21)(22)(23), over-expression of Fas ligand/TRAIL (24,25), overexpression of complement inhibitors (DAF and CD55) (26), and overexpression of HLA-G protecting against NK-induced lysis (27). A novel mechanism of tumor-derived immunosuppression through IDO has gained attention recently and has stimulated research in cancer immunology (6,7,13,28,29).…”

HLA-G gene repression is reversed by demethylation

“…The constitutive expression of HLA-G proteins in extravillous cytotrophoblasts (13), and in a few other tissues (14)(15)(16), correlates with high transcriptional activity, whereas levels of HLA-G gene transcripts are generally low or absent in other tissues (17). HLA-G is also activated in virusinfected cells (18,19), in tumoral (20)(21)(22)(23)(24)(25)(26)(27)(28)(29) and inflammatory (30)(31)(32) pathologies, and during allogenic processes (33)(34)(35).…”

Contagious cancer: Lessons from the devil and the dog

“…Non-classical MHC class I molecules, including HLA-G, are not necessarily involved in antigen presentation, tend to have limited expression in different tissues and are not necessarily polymorphic [13]. Non-classical class I molecules can act as decoys, facilitating immune evasion [14][15][16][17][18][19][20]. A classic example of this involves expression of HLA-G at the maternal-foetal interface [21].…”

“…Up-regulation of the structurally similar non-classical HLA-G prevents destruction by natural killer cells (NK), which kill cells that lack cell-surface MHC class I molecules. As will be discussed in greater detail below, this is also a common mechanism used by malignant cancers to evade the immune response [14][15][16][17][18][19][20].…”

“…The most common mechanism by which malignant cells evade the immune response is through changes in the expression patterns of classical and non-classical MHC class I and class II antigens [14][15][16][17][18][19][20]. These changes can be brought about by distinct mechanisms, including defects in b2-microglobulin synthesis, loss of genes encoding MHC heavy chains, mutations which inhibit MHC transcription or translation, defects in regulatory mechanisms which control MHC expression or abnormalities in components of the antigen processing pathway [36,37].…”