The HLA-G non classical MHC class I molecule is expressed in cancer with poor prognosis. Implications in tumour escape from immune system and clinical applications


Catherine Menier, Nathalie Rouas-Freiss, and Edgardo D. Carosella

Service de Recherche en Hémato-Immunologie
Hôpital Saint Louis
CEA - Bâtiment Lailler
1, av. Claude Vellefaux
75475 Paris Cedex 10 - France

July 2008



The HLA-G non classical MHC class I protein has been originally described as being selectively expressed on the invasive trophoblast at fetal-maternal interface at the beginning of pregnancy (Kovats et al., 1990). A few years later, HLA-G protein was detected after fertilization as early as oocyte stage (Jurisicova et al., 1996), and its presence was associated with efficient implantation of fertilized oocyte in uterine mucosa (Fuzzi et al., 2002). Its major contribution to successful pregnancy was also pointed out by both following observations : its reduced expression in pregnancy disorders such as preeclampsia and recurrent spontaneous abortion, was associated with fetal loss (Hviid, 2006) and HLA-G expression by trophoblast was shown to protect fetus from decidual NK cell attack (Rouas-Freiss et al., 1997a). Since then, the expression of HLA-G has been extended to other tissues at immune privileged sites such as: thymus (Crisa et al., 1997), cornea (Le Discorde et al., 2003), pancreas (Cirulli et al., 2006), and the erythroid and endothelial precursors (Menier et al., 2004; Menier et al., 2008). Moreover, its ability to inhibit the effectors functions of decidual NK cells has been demonstrated for allogeneic NK, T, and antigen-presenting cells (APC) (Carosella et al., 2003), which has set HLA-G as a molecule of immune tolerance. In this regard, HLA-G protein was suggested to be a way used to evade the host immune reaction in pathological situations such as infectious diseases (Favier et al., 2007), transplantation (Rouas-Freiss et al., 2007a) and cancer (Rouas-Freiss et al., 2007b).

Tumours employ different strategies to prevent immune responses including tumour-induced impairment of antigen presentation, the activation of negative co-stimulatory signals and the elaboration of immunosuppressive factors. Recently, Schreiber and colleagues (Dunn et al., 2004) propose the cancer immunoediting hypothesis which integrates the different mechanisms of tumour immune escape with the cancer immunosurveillance theory (Burnet, 1957). The cancer immunoediting concept consists of three phases: elimination, equilibrium and escape. The elimination phase corresponds to cancer immunosurveillance and implements cells from innate and adaptative immunity which recognize and destroy tumour cells. In case of partial eradication of tumour cells, equilibrium between the tumour and the immune system develops, that leads to the production of less immunogenic tumour cell clones. Finally, these tumour cell variants escape the antitumour reponse, which results in tumour growth. The expression of the immunotolerant HLA-G protein at tumour site represents one of the immunosuppressive strategies mediated by tumours.

Structural features of HLA-G

In addition to its restricted tissue distribution and its immunotolerant properties, HLA-G has structural particularities. The primary transcript of HLA-G gene is alternatively spliced producing seven mRNA encoding four membrane-bound protein isoforms: HLA-G1 to -G4 and three soluble ones: HLA-G5 to -G7 (Ishitani and Geraghty, 1992; Kirszenbaum et al., 1994; Paul et al., 2000a) (Figure 1).

At the structural level, HLA-G1 and its soluble counterpart HLA-G5 are similar to classical HLA class I protein as they include three extracellular domains, the third domain being non covalently associated to ß2-microglobulin. Therefore, among the HLA-G protein isoforms, HLA-G1 and -G5 have been the most studied. Numerous monoclonal antibodies recognizing both isoforms in their properly folded conformation have been developed (Menier et al., 2003), which allowed not only to analyze their pattern of tissue distribution but also to demonstrate the direct role of HLA-G in inhibiting immune responses, by blocking the interactions between HLA-G and its receptors (Khalil-Daher et al., 1999; Le Gal et al., 1999; Riteau et al., 2001c; Selmani et al., 2008). To date, three receptors for HLA-G have been described: one member of the killing immunoglobulin-like receptor (KIR) family : KIR2DL4, which is expressed at NK and CD8+ cell-surface (Cantoni et al., 1998; Rajagopalan et al., 1999), and two members of the immunoglobulin-like transcript (ILT) receptor family : ILT-4 (CD85d) present on myeloid cells (Colonna et al., 1998), and ILT-2, on lymphoid and myeloid cells (Colonna et al., 1997) (Figure 1). While KIR2DL4 is specific for HLA-G (Rajagopalan et al., 1999), ILT-2 and ILT-4 also bind some HLA class I alleles but with a much lower affinity than HLA-G (Shiroishi et al., 2003).

In the past few years, it has been highlighted that HLA-G1 forms dimers at cell-surface of transfected cells but also of trophoblast cells (Boyson et al., 2002; Apps et al., 2007). The HLA-G dimers exhibit higher overall affinity to ILT-2 and -4 receptors than the monomers by significant avidity effects (Gonen-Gross et al., 2003; Gonen-Gross et al., 2005; Shiroishi et al., 2006a; Shiroishi et al., 2006b), suggesting that the active conformation of HLA-G is the dimeric form (Apps et al., 2007; Gonen-Gross et al., 2003). In addition, the association of HLA-G heavy chain with ß2m is required for interaction with ILT-2, but not for binding to ILT-4 (Gonen-Gross et al., 2005; Shiroishi et al., 2006). Recently, soluble HLA-G1 (shed HLA-G1) and HLA-G5 proteins were detected in body fluids such as plasma from hepato-renal transplanted patients (Shiroishi et al., 2006b) and malignant effusions (Creput et al., 2003; Davidson et al., 2005), through the development of enzyme-linked immunosorbent assays (ELISA) of which two HLA-G-specific ones were validated during an international workshop (Rebmann et al., 2005; Rebmann et al., 2007).

The other HLA-G isoforms differs from HLA-G1 and -G5 by the lack of one (HLA-G2, -G4, and-G6 ) or two (HLA-G3 and -G7) extracellular domains (Carosella et al., 2003). Their conformational structure remains to be determined. Although their detection is still difficult, the availability of an antibody directed against a peptide in the a1 domain common to all HLA-G isoforms allowed their characterization (McMaster et al., 1998; Paul et al., 2000b; Menier et al., 2000; Lozano et al., 2002). Cell-surface expression of these truncated isoforms is probably dependent on the type of cell in which they are expressed (Mallet et al., 2000; Bainbridge et al., 2000a; Riteau et al., 2001a; Riteau et al., 2001b). Their detection as membranebound proteins was related to the same ability as the full-length HLA-G isoform to inhibit NK and antigen-specific cytotoxic T cell responses (Riteau et al., 2001b).

Functions of HLA-G protein isoforms

Through interaction with the above-described receptors, HLA-G has been shown to inhibit all the actors of the anti-tumour response (Figure 2).

Membrane-bound HLA-G reduces NK cell-mediated cytolysis, whether HLA-G is the only inhibitory ligand present on the surface of target cells (Khalil-Daher et al., 1999; Rouas-Freiss et al., 1997b), or is co-expressed with other inhibitory ligands including classical HLA class I antigens and the non classical HLA-E protein (Rouas-Freiss et al., 1997a; Riteau et al., 2001c) and/or activating ligands like the MHC class I-related chain-A (MICA) (Riteau et al., 2001b; Menier et al., 2002). HLAG also protects these target cells from antigen-specific cytotoxic T lymphocyte (CTL) activity either directly by interaction with the above-mentioned inhibitory receptors (Le Gal et al., 1999; Riteau et al., 2001b), or indirectly, by inhibiting the proliferative response of CD4+ T lymphocytes (Riteau et al., 1999), which thus leads to the decrease of the cooperation between CD4+ with CD8+ T cells. HLA-G1 is also able to exert a direct suppressive effect on CD4+ T cells (Bainbridge et al., 2000b). Furthermore, HLA-G1-expressing antigen presenting cells (APC) render CD4+ T cells anergic and the pre-sensitization of CD4+ T cells by HLA-G1+APC confers them immunosuppressive properties (LeMaoult et al., 2004; Naji et al., 2007). Recently, another mechanism inducing suppressor T or NK cells has been highlighted. These properties are acquired temporary through the rapid transfer of membrane patches (termed trogocytosis) containing HLA-G, from APC or tumour cells to T or NK cells (LeMaoult et al., 2007; Caumartin et al., 2007). Finally, cytokinemediated effects represent a means by which HLA-G can exert immunosuppression. In this regard, HLA-G influences the balance of Th(T helper)1/Th2 cytokines secretion by rather promoting Th2 type responses (Maejima et al., 1997; Kanai et al., 2001).

Like their membrane-bound counterparts, soluble HLA-G proteins (sHLA-G) have immunosuppressive properties through similar mechanisms, but with distinct characteristics. Soluble HLA-G antigens have been shown to inhibit NK cell-mediated cytotoxicity (Selmani et al., 2008; Park et al., 2004; Marchal-Bras-Goncalves et al., 2001; Poehlmann et al., 2006). Recently, following interactions between sHLA-G and the KIR2DL4 receptor on resting NK cell-surface, NK cells were shown to be activated and to release a set of chemokines and cytokines driving a proinflammatory / proangiogenic response (Rajagopalan et al., 2001). An opposite effect on angiogenesis has been observed by inducing endothelial cell apoptosis upon their binding to the CD160 (By55) receptor (Fons et al., 2006). Like soluble HLA class I antigens, through upregulation of FasL following the interactions of sHLA-G with CD8, activated T lymphocytes and NK cells come into apoptosis (Fournel et al., 2000; Contini et al., 2003). Moreover, sHLA-G inhibit the cytotoxic activity of antigen-specific CTL (Contini et al., 2003). They also decrease CD4+ and CD8+ T cell alloproliferation (Selmani et al., 2008; Contini et al., 2003; Lila et al., 2001; Le Friec et al., 2003), by blocking cell cycle progression (Bahri et al., 2006). Like its membrane-bound counterpart, naive T cells pre-sensitized by HLA-G5 differentiate into suppressor T cells (Le Rond et al., 2006). These suppressor T cells are not conventional regulatory T cells. Indeed, they express lower CD4 and CD8 antigens, which belong to the TcR/CD3 complex. Such down-modulated co-receptors T cells are hyporesponsive to allogeneic stimulus (Naji et al., 2007). Lastly, a particular property of sHLA-G is their ability to induce tolerogeneic dendritic cells associated with inhibition of their differentiation (Ristich et al., 2005). Of note, we showed that HLA-G-expressing melanoma cell lines could release exosomes which bear HLA-G together with well-described proteins as Lamp-2 (Riteau et al., 2003). The secretion of exosomes was shown to be another way for tumour to suppress immune responses (Valenti et al., 2007). Whether these HLA-G+ exosomes are immunosuppressive remains to be determined.

HLA-G expression in tumour lesions and malignant effusions

Given that HLA-G is expressed on trophoblast which is defined as a pseudo-malignant tissue, our group was the first to analyze the presence of this protein on malignant lesions. Melanoma was chosen for this study because MAGE antigens and melanoma cell adhesion molecules (Mel-CAM) are expressed in both melanoma and trophoblast cells. Moreover, this tumour was the most studied from an immunological point of view. Thus, in 1998, we described a high level of HLA-G in a skin biopsy from melanoma metastasis and in a melanoma cell line for which presence of HLA-G was related to protection from NK lysis (Paul et al., 1998). Two following studies on two hundred patients melanoma biopsies revealed that: (i) HLA-G protein was expressed in thirty percent of the patients (Paul et al., 1999; Ibrahim el et al., 2004), (ii) HLA-G expression is associated with malignant transformation of melanocyte as this protein was detected in both primary and metastatic tumour sites, but neither in adjacent tumour tissue or in spontaneous tumour regression site or in healthy skin (Paul et al., 1999; Ibrahim el et al., 2004), (iii) higher levels of inflammatory tumour-infiltrating cells were observed in malignant melanoma lesions in comparison to begnin ones (Ibrahim el et al., 2004) and (iv) up-regulation of HLA-G in melanocytes is a better predictor of malignancy than classical HLA class I antigens defects, (Ibrahim el et al., 2004) which are often described as an important mechanism of tumour escape from immunosurveillance (Ferrone and Marincola, 1995). This association between the presence of HLA-G and the malignant nature of the tumour suggested that HLA-G was a mechanism for tumours to escape immune surveillance.

Following our first description, HLA-G expression in melanoma lesions was confirmed by other groups and numerous other tumour lesion types of either ectodermic or mesodermic or endodermic origin were studied. Today, in about two thousand patients analyzed, HLA-G protein was found in almost all types of cancer whatever their origin, but in varying proportions ranging between 10% (leukemia) to 95% (esophageal squamous cell carcinoma) (Figure 3).

A recent review summarizes HLA-G protein expression in tumour lesions (Carosella et al., 2008). Since that review, among 140 patients with lung cancer analyzed, approximately 60% of them expressed HLA-G protein. Two other types of cancers were studied: in 175 patients with classical Hodgkin lymphoma, HLA-G protein was found in 50% of cases and in 121 patients with esophageal squamous cell carcinoma, this proportion reached 95%. This heterogeneity may reflect the differences in the biology of individual tumours, in study design and/or the sensitivity of the methods used to detect HLA-G protein in malignant lesions. HLA-G expression is also heterogeneous within a tumour type and within individual lesions. Indeed, HLA-G has been detected in the tumour tissue and/or in the infiltrating lymphocytes in tumours such as melanoma (Ibrahim et al., 2003), breast cancer (Lefebvre et al., 2002), and lung carcinoma (Urosevic et al., 2001). Moreover, HLA-G expression can concern different number of cells within a type of tumour according to the patients (Ibrahim el et al., 2004; Nuckel et al., 2005).

Through the recent development of HLA-G-specific ELISA, high levels of HLA-G in its soluble form have also been detected in the plasma of patients with various cancers (Rebmann et al., 2003), including melanoma (Ugurel et al., 2001), glioma (Wiendl et al., 2002), multiple myeloma (Leleu et al., 2005), lymphoblastic and monocytic acute leukaemia (Amiot et al., 2003; Gros et al., 2006), neuroblastoma (Morandi et al., 2007), and in ascites from breast and ovarian carcinomas (Singer et al., 2003).

Regulation of HLA-G expression in cancer

Up to date, in more than two hundred cell lines derived from malignant tumour biopsies, HLA-G protein was only detected in about ten ones, what contrasts with the proportion of surgically removed malignant tumour lesions which express HLA-G (Rouas-Freiss et al., 2003). This discrepancy shows that in vitro, factors which were maintaining the expression of HLA-G are not present anymore, and that in vivo, HLA-G expression is activated by environmental stimuli such as stress conditions, cytokines and epigenetic variations.

Indeed, like MICA genes, we showed that HLA-G is a stress-inducible gene. Heat shock and arsenite induced an increase of the different HLA-G alternative transcripts without affecting the other MHC class I HLA-A, -B, -C, -E and -F transcripts in melanoma cells (Ibrahim et al., 2000). A stress situation is represented by hypoxia, which exists in the surrounding microenvironment of rapidly growing tumours. Hypoxia was shown to induce the hypoxia-inducible factor-1a (HIF-1a) which can in turn, trigger the transcription and traduction of HLA-G gene in HLA G-tumour cells (Chang and Ferrone, 2003; Mouillot et al., 2007; Gazit et al., 2007). In contrast, HLA-G expression was decreased in HLA-G+ tumour cells (Mouillot et al., 2007). In both up- and down-modulation, HLA-G expression depends on HIF-1a stabilization (Mouillot et al., 2007). Finally, it is well-known that both the depletion of the essential amino acid tryptophan and the accumulation of tryptophan metabolites from the microenvironment provokes an inhibition of immune cells function. This represents another tumour escape mechanism from immune system as some tumours or APC in tumour-draining lymph nodes express the indolamine 2,3-dioxygenase (IDO), an enzyme which metabolizes tryptophan (Friberg et al., 2002; Uyttenhove et al., 2003; Munn and Mellor, 2007; Munn et al., 2004). Searching for a link between HLA-G and IDO molecules, we found that (i) inhibiting the function of IDO up-regulates HLA-G1 cell-surface expression on APC and tumour cell lines (Gonzalez-Hernandez et al., 2005), (ii) IDO induces HLA-G expression during monocyte differentiation into dendritic cells (Lopez et al., 2006), and (iii) IDO and HLA-G inhibit T cell alloproliferation through two independent but complementary pathways (Le Rond et al., 2005). Thus, the recent development of IDO inhibitors as a new immunoregulatory treatment modality for clinical trials (Katz et al., 2008) has to consider the possible stimulation of HLA-G expression.

Numerous studies have investigated the cytokine-mediated induction of HLA-G expression. Particularly, the anti-inflammatory and immunosuppressive IL-10 cytokine secretion by lung carcinoma cells and T and B lymphoma cells has been correlated with concomitant HLA-G expression (Urosevic et al., 2001; Urosevic et al., 2002). Transactivation of HLA-G transcription has also been demonstrated by JEG3 choriocarcinoma cell exposure to leukemia inhibitory factor (LIF) (Bamberger et al., 2000). Furthermore, interferon (IFN)-a, -ß and -γ enhance HLA-G cell-surface expression by tumours or monocytes (Ugurel et al., 2001; Lefebvre et al., 1999; Lefebvre et al., 2001; Wagner et al., 2000; Moreau et al., 1999; Bukur et al., 2003). This up-regulation of HLA-G at the tumour site represents one potential side effect of the administration of IFN for immunotherapy and may confer immunoprotection to tumour cells, thus favouring tumour expansion. In this regard, an association has been established between the lack of clinical response to therapy with IFN-a high doses and HLAG expression in melanoma lesions (Wagner et al., 2000). The expression of inflammatory cytokines such as IFN-γ is under the control of the nuclear factor-κB (NF-κB), a pivotal transcription factor of innate and adaptative immunity. In addition, NF-κB signaling also plays a critical role in cancer development and progression (Karin and Greten, 2005). Thus, we analyzed whether NF-κB and HLA-G were linked and demonstrated that NF-κB activation enhances HLA-G intracytoplasmic tumour cell content, but promotes the proteolytic shedding of membrane-bound HLA-G (Zidi et al., 2006). Moreover, we showed that HLA-G1+ tumour cells activate NF-κB in NK cells. This activation occurs through interactions between the a1 domain of HLA-G and presumably the KIR2DL4 receptor (Guillard et al., 2008).

Remarkably, cytokines have no effect on HLA-G gene transcription in tumour cells in which this gene is repressed (Frumento et al., 2000). This led us to propose the hypothesis of the existence of epigenetic mechanisms, which may activate the HLA-G gene in some tumours. Global genomic hypomethylation occurs frequently during carcinogenesis and genetic lesions in methyl-chromatin-related genes, such as histone deacetylase, are supposed to influence the epigenetic alterations involved in cancer (Esteller et al., 2002; Esteller and Herman, 2002). We showed that exposure of some tumours cell lines to histone deacetylase inhibitors, or the decitabine DNA demethylating agent, reactivate both HLA-G gene transcription and traduction (Moreau et al., 2003; Mouillot et al., 2005; Yan et al., 2005). Thus, the HLA-G gene derepression must be considered as adverse effect following chemotherapy with drugs such as decitabine, which are currently used to reactivate tumour suppressor genes and other genes involved in invasion and metastasis (Maio et al., 2003).

HLA-G in cancer immunoediting

During the elimination phase which matches with cancer immunosurveillance, classical HLA class I expression at tumour cell-surface is supposed to be unchanged. Tumour-infiltrating lymphocytes and NK cells produce Th1-type cytokines. Particularly, IFN-gamma is one of the cytokines up-regulating HLA-G expression in tumour cells either directly or indirectly through induction of IDO. Towards its predominant inhibitory role, HLA-G could greatly weaken host anti-tumoural immune responses.

During the equilibrium phase which corresponds to cancer persistence, epigenetic changes take place frequently and contribute to the development of non immunogenic tumour cell clones. At present, in vitro studies showed that demethylation and histone deacetylation reverses HLA-G gene silencing. In addition to its direct inhibitory role on immune cells, HLA-G protein may also play this role indirectly through the plasma membrane stabilization of the non classical CMH class I HLA-E protein (Khalil-Daher et al., 1999; Riteau et al., 2001b; Borrego et al., 1998). HLA-E reaches cell surface through binding of MHC class I leader peptide (Braud et al., 1997; Braud et al., 1998; Lee et al., 1998). Although classical HLA class I molecules can be completely lost, HLA-G can mediate the membrane expression of HLA-E, which confers additional protection of tumour cells to NK cytolysis. Moreover, HLA-G also contributes to the already altered antigen presentation (Wright and Ting, 2006) by down-modulating HLA class II molecules on APC (Ristich et al., 2005).

The escape phase in which cancer progresses, is the phase where HLA-G is preferentially expressed comparatively to initial malignant tumour lesions. Tumours generate an appropriate microenvironment that allows them to prevent their immune cell elimination, thus favouring their growth. The mechanisms to achieve this goal include the modulation of antigen expression that allows preventing activation of the immune system, the induction of peripheral tolerance by induction of anergy or induction of immunosuppressor cells, and the production of immunosuppressive cytokines. HLA-G plays a significant role in these mechanisms because HLA-G remains the almost single-molecule expressed by tumours. In addition to local effects at its site of expression, secreted soluble HLA-G could also have systemic inhibitory activity through its distribution in blood circulation. Among the immunosuppressive cytokines produced by tumours, IL-10 is responsible for HLA-G up-regulation in cancer. Both IL-10 and HLA-G may be produced by tumour cells themselves or by tumour-infiltrating cells. There is an amplification loop since both IL-10-induced decrease of the production of Th1-type cytokine and HLA-G expression are able to increase IL-10 production. Moreover, HLA-G was shown to increase its own inhibitory receptors in NK, APC and T effector cells (LeMaoult et al., 2005), and IL-10 can also modulate the KIR repertoire on NK and T cells, what further contribute to dampen immune responses. During this phase, chronic inflammation is assumed to favour tumour growth through activation of NF-κB, which may enhance systemic inhibitory action through the release of soluble HLA-G1 from proteolytic shedding of membrane HLA-G1. The rapid tumour cell proliferation creates a hypoxic microenvironment, a stress condition which also promotes tumour invasion per se but in addition, by inducing HLA-G expression. Importantly, some therapeutic strategies, as either immunotherapy using IFN-a, or chemotherapy with DNA-demethylating or histone deacetylating agents, or therapeutic vaccination using IDO inhibitors, must be revisited since these treatments were shown to upregulate HLA-G.

Biological relevance of HLA-G expression in cancer

In vitro studies have shown that HLA-G-endogenously expressing melanoma, glioma and renal carcinoma cell lines are protected from lysis by alloreactive NK and lymphokineactivated killer cells and/or antigen-specific CD8+ T cells (Paul et al., 1998; Wiendl et al., 2002; Bukur et al., 2003). This protective effect was directly due to HLA-G expression by tumour cells since the blockade of this molecule restored the cytotoxic activity of effector cells. Since then, two studies have reinforced the role of HLA-G in tumours. In the first study, we derived a HLA-G+ melanoma cell line, called Fon, from a HLA-G+ melanoma biopsy (Rouas-Freiss et al., 2005). The Fon cell line expressed high levels of membrane-bound HLA-G1, which confers resistance to NK cell line lysis through interaction with ILT-2 inhibitory receptor. During the long-term spread of Fon cells in culture, the expression of HLA-G1 has been lost, as was its protection against the NK cell cytotoxicity. Although IFN-ß, -γ or decitabine treatments enhanced HLAG1 expression in the primary Fon cells, neither these cytokines, nor this DNA-demethylating drug brought back HLA-G1 transcription. Altogether, these results emphasize the difficulty using cell lines derived from tumour biopsies to establish the physiopathological relevance of HLA-G in anti-tumour responses since HLA-G expression can be lost during long-term tumour expansion. Moreover, they support the role of HLA-G1 expressed at tumour cellsurface in preventing host innate immune cell responses.
As described for other tumour type, the second study showed that neuroblastoma patients had significant higher serum levels of sHLA-G than healthy donors. The source of sHLA-G in neuroblastoma patients was not tumour cells but monocytes in an activated state. The sHLA-G produced was able to inhibit CTL and NK cell-mediated cytotoxicity against tumour cells. Interestingly, the sHLA-G-secreting monocytes were instructed by neuroblastoma cells through the release of soluble factors that may be IL-10 or TGF-ß1. These monocytes display features of macrophage-like activated cells but shift towards a more anergic phenotype since they secrete higher levels of immunosuppressive sHLA-G and lower IL-12, a cytokine which promotes anti-tumour responses. These findings support an in vivo systemic effect of HLA-G in cancer (Morandi et al., 2007), and provide guidance on a novel mechanism of tumour immune evasion.

Clinical significance of HLA-G expression in cancer

As above described, HLA-G expression has always been detected in malignant tissues or effusions and has never been found neither in healthy tumour surrounded areas, nor in tissues or effusions from patients suffering of begnin disease, nor in the corresponding tissues from healthy individuals (Ibrahim el et al., 2004; Ibrahim et al., 2003; Singer et al., 2003; Aractingi et al., 2003). In melanoma, upregulation of HLA-G molecules in melanocytic cells appears as a better predictor of malignancy than classical HLA class I antigen defects frequently observed in this cancer type (Ibrahim el et al., 2004).

The idea that HLA-G expression could be a prognostic factor has emerged recently. Indeed, HLA-G expression and/or sHLA-G high levels have been significantly correlated with poor prognosis in non-small cell lung cancer, melanoma, glioblastoma, ovarian carcinoma, B-CLL, cutaneous T cell lymphoma, neuroblastoma and digestive cancers (Urosevic et al., 2001; Nuckel et al., 2005; Ugurel et al., 2001; Wiendl et al., 2002; Morandi et al., 2007; Singer et al., 2003; Urosevic et al., 2002; Yie et al., 2007a; Yie et al., 2007b; Ye et al., 2007; Yie et al., 2007c). In particular, in ovarian carcinomas, high levels of soluble HLA-G protein were measured in the effusions produced in late-stage disease which overlaps with the first appearance of metastases (Singer et al., 2003). In digestive cancers and B-CLL, HLA-G expression was shown as being an independent prognostic factor (Nuckel et al., 2005; Yie et al., 2007b; Ye et al., 2007; Yie et al., 2007c). In multivariate analysis of B-CLL patients, HLA-G expression was an even better independent prognostic factor than the zeta-associated protein 70 (ZAP-70) or CD38 status (Nuckel et al., 2005). Finally, the role of HLA-G in tumour escape from host immune cell is emphasized by its involvement of the resistance to IFN therapy observed in some melanoma patients (Wagner et al., 2000).

Conclusion and perspectives

Towards its immunotolerant properties, HLA-G expression is an additional but efficient way for tumour to evade immunosurveillance. In the few last years, the clinical relevance of HLAG has been established in cancer. Indeed, HLA-G was always correlated with higher grade histology and advanced disease stage, and for the most complete studies, increased depth of invasion, more frequent lymph node metastasis, reduced host immune response and shortened survival. However, multicenter studies including larger cohorts of patients are needed to demonstrate the usefulness of HLA-G levels quantification in predicting the clinical outcome of cancer patients. Since clinical studies clearly reveal a negative correlation between HLA-G and patient survival, HLA-G appears an attractive molecular target to develop new anti-tumour therapies. The reverse of tumour growth might be obtained through blockade of HLA-G synthesis by preventing its transcription using silencing RNA or acting on HLA-G alternative splicing (Rouas-Freiss et al., 2005), or through restoration of host immune responses by using antibodies neutralizing interactions between HLA-G and its receptors. Thus, the in vivo validation of the proof-of-concept requires the development of a tumour model in mice since although a true HLA-G homolog is lacking, murine PIR-B can bind HLA-G allowing such model to be evaluated there is a HLAG inhibitory receptor homolog (Liang et al., 2002; Ungchusri et al., 2001; Comiskey et al., 2003; Chiang et al., 2002; Chiang and Stroynowski, 2005).


Cancer; a biological approach. I. The processes of control.
Burnet M.
Br Med J. 1957 Apr 6;1(5022):779-86.
PMID 13404306
A class I antigen, HLA-G, expressed in human trophoblasts.
Kovats S, Main EK, Librach C, Stubblebine M, Fisher SJ, DeMars R.
Science. 1990 Apr 13;248(4952):220-3.
PMID 2326636
Alternative splicing of HLA-G transcripts yields proteins with primary structures resembling both class I and class II antigens.
Ishitani A, Geraghty DE.
Proc Natl Acad Sci U S A. 1992 May 1;89(9):3947-51.
PMID 1570318
An alternatively spliced form of HLA-G mRNA in human trophoblasts and evidence for the presence of HLA-G transcript in adult lymphocytes.
Kirszenbaum M, Moreau P, Gluckman E, Dausset J, Carosella E.
Proc Natl Acad Sci U S A. 1994 May 10;91(10):4209-13.
PMID 8183892
Loss of HLA class I antigens by melanoma cells: molecular mechanisms, functional significance and clinical relevance.
Ferrone S, Marincola FM.
Immunol Today. 1995 Oct;16(10):487-94.
PMID 7576053
Embryonic human leukocyte antigen-G expression: possible implications for human preimplantation development.
Jurisicova A, Casper RF, MacLusky NJ, Librach CL.
Fertil Steril. 1996 May;65(5):997-1002.
PMID 8612864
The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9.
Braud V, Jones EY, McMichael A.
Eur J Immunol. 1997 May;27(5):1164-9.
PMID 9174606
A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells.
Colonna M, Navarro F, Bellon T, Llano M, Garcia P, Samaridis J, Angman L, Cella M, Lopez-Botet M.
J Exp Med. 1997 Dec 1;186(11):1809-18.
PMID 9382880
Identification of a thymic epithelial cell subset sharing expression of the class Ib HLA-G molecule with fetal trophoblasts.
Crisa L, McMaster MT, Ishii JK, Fisher SJ, Salomon DR.
J Exp Med. 1997 Jul 21;186(2):289-98.
PMID 9221758
Presence of HLA-G-expressing cells modulates the ability of peripheral blood mononuclear cells to release cytokines.
Maejima M, Fujii T, Kozuma S, Okai T, Shibata Y, Taketani Y.
Am J Reprod Immunol. 1997 Aug;38(2):79-82.
PMID 9272204
Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis.
Rouas-Freiss N, GoníZalves RM, Menier C, Dausset J, Carosella ED.
Proc Natl Acad Sci U S A. 1997a Oct 14;94(21):11520-5.
PMID 9326642
The alpha1 domain of HLA-G1 and HLA-G2 inhibits cytotoxicity induced by natural killer cells: is HLA-G the public ligand for natural killer cell inhibitory receptors?
Rouas-Freiss N, Marchal RE, Kirszenbaum M, Dausset J, Carosella ED.
Proc Natl Acad Sci U S A. 1997b May 13;94(10):5249-54.
PMID 9144223
Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis.
Borrego F, Ulbrecht M, Weiss EH, Coligan JE, Brooks AG.
J Exp Med. 1998 Mar 2;187(5):813-8.
PMID 9480992
TAP- and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide.
Braud VM, Allan DS, Wilson D, McMichael AJ.
Curr Biol. 1998 Jan 1;8(1):1-10.
PMID 9427624
p49, a putative HLA class I-specific inhibitory NK receptor belonging to the immunoglobulin superfamily.
Cantoni C, Verdiani S, Falco M, Pessino A, Cilli M, Conte R, Pende D, Ponte M, Mikaelsson MS, Moretta L, Biassoni R.
Eur J Immunol. 1998 Jun;28(6):1980-90.
PMID 9645380
Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules.
Colonna M, Samaridis J, Cella M, Angman L, Allen RL, O'Callaghan CA, Dunbar R, Ogg GS, Cerundolo V, Rolink A.
J Immunol. 1998 Apr 1;160(7):3096-100.
PMID 9531263
HLA-E surface expression depends on binding of TAP-dependent peptides derived from certain HLA class I signal sequences.
Lee N, Goodlett DR, Ishitani A, Marquardt H, Geraghty DE.
J Immunol. 1998 May 15;160(10):4951-60.
PMID 9590243
HLA-G isoforms produced by placental cytotrophoblasts and found in amniotic fluid are due to unusual glycosylation.
McMaster M, Zhou Y, Shorter S, Kapasi K, Geraghty D, Lim KH, Fisher S.
J Immunol. 1998 Jun 15;160(12):5922-8.
PMID 9637505
HLA-G expression in melanoma: a way for tumor cells to escape from immunosurveillance.
Paul P, Rouas-Freiss N, Khalil-Daher I, Moreau P, Riteau B, Le Gal FA, Avril MF, Dausset J, Guillet JG, Carosella ED.
Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4510-5.
PMID 9539768
Role of HLA-G versus HLA-E on NK function: HLA-G is able to inhibit NK cytolysis by itself.
Khalil-Daher I, Riteau B, Menier C, Sedlik C, Paul P, Dausset J, Carosella ED, Rouas-Freiss N.
J Reprod Immunol. 1999 Jul;43(2):175-82.
PMID 10479053
Molecular mechanisms controlling constitutive and IFN-gamma-inducible HLA-G expression in various cell types.
Lefebvre S, Moreau P, Guiard V, Ibrahim EC, Adrian-Cabestre F, Menier C, Dausset J, Carosella ED, Paul P.
J Reprod Immunol. 1999 Jul;43(2):213-24.
PMID 10479057
HLA-G-mediated inhibition of antigen-specific cytotoxic T lymphocytes.
Le Gal FA, Riteau B, Sedlik C, Khalil-Daher I, Menier C, Dausset J, Guillet JG, Carosella ED, Rouas-Freiss N.
Int Immunol. 1999 Aug;11(8):1351-6.
PMID 10421792
IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes.
Moreau P, Adrian-Cabestre F, Menier C, Guiard V, Gourand L, Dausset J, Carosella ED, Paul P.
Int Immunol. 1999 May;11(5):803-11.
PMID 10330285
Heterogeneity of HLA-G gene transcription and protein expression in malignant melanoma biopsies.
Paul P, Cabestre FA, Le Gal FA, Khalil-Daher I, Le Danff C, Schmid M, Mercier S, Avril MF, Dausset J, Guillet JG, Carosella ED.
Cancer Res. 1999 Apr 15;59(8):1954-60.
PMID 10213506
A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells.
Rajagopalan S, Long EO.
J Exp Med. 1999 Apr 5;189(7):1093-100.
PMID 10190900
HLA-G inhibits the allogeneic proliferative response.
Riteau B, Menier C, Khalil-Daher I, Sedlik C, Dausset J, Rouas-Freiss N, Carosella ED.
J Reprod Immunol. 1999 Jul;43(2):203-11.
PMID 10479056
The short forms of HLA-G are unlikely to play a role in pregnancy because they are not expressed at the cell surface.
Bainbridge DR, Ellis SA, Sargent IL.
J Reprod Immunol. 2000a May;47(1):1-16.
PMID 10779586
HLA-G suppresses proliferation of CD4(+) T-lymphocytes.
Bainbridge DR, Ellis SA, Sargent IL.
J Reprod Immunol. 2000b Aug;48(1):17-26.
PMID 10996380
Leukemia inhibitory factor (LIF) stimulates the human HLA-G promoter in JEG3 choriocarcinoma cells.
Bamberger AM, Jenatschke S, Schulte HM, Loning T, Bamberger MC.
J Clin Endocrinol Metab. 2000 Oct;85(10):3932-6.
PMID 11061559
Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8.
Fournel S, Aguerre-Girr M, Huc X, Lenfant F, Alam A, Toubert A, Bensussan A, Le Bouteiller P.
J Immunol. 2000 Jun 15;164(12):6100-4.
PMID 10843658
Melanomas and melanoma cell lines do not express HLA-G, and the expression cannot be induced by gammaIFN treatment.
Frumento G, Franchello S, Palmisano GL, Nicotra MR, Giacomini P, Loke YW, Geraghty DE, Maio M, Manzo C, Natali PG, Ferrara GB.
Tissue Antigens. 2000 Jul;56(1):30-7.
PMID 10958353
Heat shock and arsenite induce expression of the nonclassical class I histocompatibility HLA-G gene in tumor cell lines.
Ibrahim EC, Morange M, Dausset J, Carosella ED, Paul P.
Cell Stress Chaperones. 2000 Jul;5(3):207-18.
PMID 11005379
The full length HLA-G1 and no other alternative form of HLA-G is expressed at the cell surface of transfected cells.
Mallet V, Proll J, Solier C, Aguerre-Girr M, DeRossi M, Loke YW, Lenfant F, Le Bouteiller P.
Hum Immunol. 2000 Mar;61(3):212-24.
PMID 10689111
HLA-G truncated isoforms can substitute for HLA-G1 in fetal survival.
Menier C, Riteau B, Dausset J, Carosella ED, Rouas-Freiss N.
Hum Immunol. 2000 Nov;61(11):1118-25.
PMID 11137216
Identification of HLA-G7 as a new splice variant of the HLA-G mRNA and expression of soluble HLA-G5, -G6, and -G7 transcripts in human transfected cells.
Paul P, Cabestre FA, Ibrahim EC, Lefebvre S, Khalil-Daher I, Vazeux G, Quiles RM, Bermond F, Dausset J, Carosella ED.
Hum Immunol. 2000a Nov;61(11):1138-49.
PMID 11137219
HLA-G, -E, -F preworkshop: tools and protocols for analysis of non-classical class I genes transcription and protein expression.
Paul P, Rouas-Freiss N, Moreau P, Cabestre FA, Menier C, Khalil-Daher I, Pangault C, Onno M, Fauchet R, Martinez-Laso J, Morales P, Villena AA, Giacomini P, Natali PG, Frumento G, Ferrara GB, McMaster M, Fisher S, Schust D, Ferrone S, Dausset J, Geraghty D, Carosella ED.
Hum Immunol. 2000b Nov;61(11):1177-95.
PMID 11137224
Expression analysis of classic and non-classic HLA molecules before interferon alfa-2b treatment of melanoma.
Wagner SN, Rebmann V, Willers CP, Grosse-Wilde H, Goos M.
Lancet. 2000 Jul 15;356(9225):220-1.
PMID 10963203
Human leukocyte antigen-G-expressing cells differently modulate the release of cytokines from mononuclear cells present in the decidua versus peripheral blood.
Kanai T, Fujii T, Unno N, Yamashita T, Hyodo H, Miki A, Hamai Y, Kozuma S, Taketani Y.
Am J Reprod Immunol. 2001 Feb;45(2):94-9.
PMID 11216880
A specific interferon (IFN)-stimulated response element of the distal HLA-G promoter binds IFN-regulatory factor 1 and mediates enhancement of this nonclassical class I gene by IFN-beta.
Lefebvre S, Berrih-Aknin S, Adrian F, Moreau P, Poea S, Gourand L, Dausset J, Carosella ED, Paul P.
J Biol Chem. 2001 Mar 2;276(9):6133-9. Epub 2000 Nov 21.
PMID 11087747
Soluble HLA-G protein secreted by allo-specific CD4+ T cells suppresses the allo-proliferative response: a CD4+ T cell regulatory mechanism.
Lila N, Rouas-Freiss N, Dausset J, Carpentier A, Carosella ED.
Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12150-5. Epub 2001 Sep 25.
PMID 11572934
A soluble HLA-G protein that inhibits natural killer cell-mediated cytotoxicity.
Marchal-Bras-Goncalves R, Rouas-Freiss N, Connan F, Choppin J, Dausset J, Carosella ED, Kirszenbaum M, Guillet J.
Transplant Proc. 2001 May;33(3):2355-9.
PMID 11377558
Cutting edge: induction of IFN-gamma production but not cytotoxicity by the killer cell Ig-like receptor KIR2DL4 (CD158d) in resting NK cells.
Rajagopalan S, Fu J, Long EO.
J Immunol. 2001 Aug 15;167(4):1877-81.
PMID 11489965
Characterization of HLA-G1, -G2, -G3, and -G4 isoforms transfected in a human melanoma cell line.
Riteau B, Moreau P, Menier C, Khalil-Daher I, Khosrotehrani K, Bras-Goncalves R, Paul P, Dausset J, Rouas-Freiss N, Carosella ED.
Transplant Proc. 2001a May;33(3):2360-4.
PMID 11377559
HLA-G2, -G3, and -G4 isoforms expressed as nonmature cell surface glycoproteins inhibit NK and antigen-specific CTL cytolysis.
Riteau B, Rouas-Freiss N, Menier C, Paul P, Dausset J, Carosella ED.
J Immunol. 2001b Apr 15;166(8):5018-26.
PMID 11290782
HLA-G1 co-expression boosts the HLA class I-mediated NK lysis inhibition.
Riteau B, Menier C, Khalil-Daher I, Martinozzi S, Pla M, Dausset J, Carosella ED, Rouas-Freiss N.
Int Immunol. 2001c Feb;13(2):193-201.
PMID 11157852
Soluble human leukocyte antigen--G serum level is elevated in melanoma patients and is further increased by interferon-alpha immunotherapy.
Ugurel S, Rebmann V, Ferrone S, Tilgen W, Grosse-Wilde H, Reinhold U.
Cancer. 2001 Jul 15;92(2):369-76.
PMID 11466692
Widespread expression of the nonclassical class I Qa-2 antigens in hemopoietic and nonhemopoietic cells.
Ungchusri T, Chiang EY, Brown G, Chen M, Tabaczewski P, Timares L, Stroynowski I.
Immunogenetics. 2001 Aug;53(6):455-67.
PMID 11685456
Human leukocyte antigen G up-regulation in lung cancer associates with high-grade histology, human leukocyte antigen class I loss and interleukin-10 production.
Urosevic M, Kurrer MO, Kamarashev J, Mueller B, Weder W, Burg G, Stahel RA, Dummer R, Trojan A.
Am J Pathol. 2001 Sep;159(3):817-24.
PMID 11549573
Disulfide bond-mediated dimerization of HLA-G on the cell surface.
Boyson JE, Erskine R, Whitman MC, Chiu M, Lau JM, Koopman LA, Valter MM, Angelisova P, Horejsi V, Strominger JL.
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16180-5. Epub 2002 Nov 26.
PMID 12454284
The nonclassical major histocompatibility complex molecule Qa-2 protects tumor cells from NK cell- and lymphokine-activated killer cell-mediated cytolysis.
Chiang EY, Henson M, Stroynowski I.
J Immunol. 2002 Mar 1;168(5):2200-11.
PMID 11859106
Cancer epigenetics and methylation.
Esteller M, Fraga MF, Paz MF, Campo E, Colomer D, Novo FJ, Calasanz MJ, Galm O, Guo M, Benitez J, Herman JG.
Science. 2002 Sep 13;297(5588):1807-8; discussion 1807-8.
PMID 12229925
Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours.
Esteller M, Herman JG.
J Pathol. 2002 Jan;196(1):1-7.
PMID 11748635
Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection.
Friberg M, Jennings R, Alsarraj M, Dessureault S, Cantor A, Extermann M, Mellor AL, Munn DH, Antonia SJ.
Int J Cancer. 2002 Sep 10;101(2):151-5.
PMID 12209992
HLA-G expression in early embryos is a fundamental prerequisite for the obtainment of pregnancy.
Fuzzi B, Rizzo R, Criscuoli L, Noci I, Melchiorri L, Scarselli B, Bencini E, Menicucci A, Baricordi OR.
Eur J Immunol. 2002 Feb;32(2):311-5.
PMID 11807769
Specific activation of the non-classical class I histocompatibility HLA-G antigen and expression of the ILT2 inhibitory receptor in human breast cancer.
Lefebvre S, Antoine M, Uzan S, McMaster M, Dausset J, Carosella ED, Paul P.
J Pathol. 2002 Mar;196(3):266-74.
PMID 11857488
HLA-G inhibits the functions of murine dendritic cells via the PIR-B immune inhibitory receptor.
Liang S, Baibakov B, Horuzsko A.
Eur J Immunol. 2002 Sep;32(9):2418-26.
PMID 12207326
Monocytes and T lymphocytes in HIV-1-positive patients express HLA-G molecule.
Lozano JM, Gonzalez R, Kindelan JM, Rouas-Freiss N, Caballos R, Dausset J, Carosella ED, Pena J.
AIDS. 2002 Feb 15;16(3):347-51.
PMID 11834945
MICA triggering signal for NK cell tumor lysis is counteracted by HLA-G1-mediated inhibitory signal.
Menier C, Riteau B, Carosella ED, Rouas-Freiss N.
Int J Cancer. 2002 Jul 1;100(1):63-70.
PMID 12115588
HLA-G protein up-regulation in primary cutaneous lymphomas is associated with interleukin-10 expression in large cell T-cell lymphomas and indolent B-cell lymphomas.
Urosevic M, Willers J, Mueller B, Kempf W, Burg G, Dummer R.
Blood. 2002 Jan 15;99(2):609-17.
PMID 11781245
A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape.
Wiendl H, Mitsdoerffer M, Hofmeister V, Wischhusen J, Bornemann A, Meyermann R, Weiss EH, Melms A, Weller M.
J Immunol. 2002 May 1;168(9):4772-80.
PMID 11971028
HLA-G and lymphoproliferative disorders.
Amiot L, Le Friec G, Sebti Y, Drenou B, Pangault C, Guilloux V, Leleu X, Bernard M, Facon T, Fauchet R.
Semin Cancer Biol. 2003 Oct;13(5):379-85.
PMID 14708718
Selective expression of HLA-G in malignant and premalignant skin specimens in kidney transplant recipients.
Aractingi S, Kanitakis J, Euvrard S, Le Danff C, Carosella ED.
Int J Cancer. 2003 Aug 20;106(2):232-5.
PMID 12800199
Functional role of human leukocyte antigen-G up-regulation in renal cell carcinoma.
Bukur J, Rebmann V, Grosse-Wilde H, Luboldt H, Ruebben H, Drexler I, Sutter G, Huber C, Seliger B.
Cancer Res. 2003 Jul 15;63(14):4107-11.
PMID 12874014
HLA-G molecules: from maternal-fetal tolerance to tissue acceptance.
Carosella ED, Moreau P, Le Maoult J, Le Discorde M, Dausset J, Rouas-Freiss N.
Adv Immunol. 2003;81:199-252.
PMID 14711057
HLA-G in melanoma: can the current controversies be solved?
Chang CC, Ferrone S.
Semin Cancer Biol. 2003 Oct;13(5):361-9.
PMID 14708716
Evidence that HLA-G is the functional homolog of mouse Qa-2, the Ped gene product.
Comiskey M, Goldstein CY, De Fazio SR, Mammolenti M, Newmark JA, Warner CM.
Hum Immunol. 2003 Nov;64(11):999-1004.
PMID 14602227
Soluble HLA-A,-B,-C and -G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation.
Contini P, Ghio M, Poggi A, Filaci G, Indiveri F, Ferrone S, Puppo F.
Eur J Immunol. 2003 Jan;33(1):125-34.
PMID 12594841
Detection of HLA-G in serum and graft biopsy associated with fewer acute rejections following combined liver-kidney transplantation: possible implications for monitoring patients.
Creput C, Le Friec G, Bahri R, Amiot L, Charpentier B, Carosella E, Rouas-Freiss N, Durrbach A.
Hum Immunol. 2003 Nov;64(11):1033-8.
PMID 14602232
Complexes of HLA-G protein on the cell surface are important for leukocyte Ig-like receptor-1 function.
Gonen-Gross T, Achdout H, Gazit R, Hanna J, Mizrahi S, Markel G, Goldman-Wohl D, Yagel S, Horejs V, Levy O, Baniyash M, Mandelboim O.
J Immunol. 2003 Aug 1;171(3):1343-51.
PMID 12874224
Altered pattern of major histocompatibility complex expression in renal carcinoma: tumor-specific expression of the nonclassical human leukocyte antigen-G molecule is restricted to clear cell carcinoma while up-regulation of other major histocompatibility complex antigens is primarily distributed in all subtypes of renal carcinoma.
Ibrahim el C, Allory Y, Commo F, Gattegno B, Callard P, Paul P.
Am J Pathol. 2003 Feb;162(2):501-8.
PMID 12547708
Expression of HLA-G in human cornea, an immune-privileged tissue.
Le Discorde M, Moreau P, Sabatier P, Legeais JM, Carosella ED.
Hum Immunol. 2003 Nov;64(11):1039-44.
PMID 14602233
Soluble HLA-G inhibits human dendritic cell-triggered allogeneic T-cell proliferation without altering dendritic differentiation and maturation processes.
Le Friec G, Laupeze B, Fardel O, Sebti Y, Pangault C, Guilloux V, Beauplet A, Fauchet R, Amiot L.
Hum Immunol. 2003 Aug;64(8):752-61.
PMID 12878353
Epigenetic targets for immune intervention in human malignancies.
Maio M, Coral S, Fratta E, Altomonte M, Sigalotti L.
Oncogene. 2003 Sep 29;22(42):6484-8.
PMID 14528272
Characterization of monoclonal antibodies recognizing HLA-G or HLA-E: new tools to analyze the expression of nonclassical HLA class I molecules.
Menier C, Saez B, Horejsi V, Martinozzi S, Krawice-Radanne I, Bruel S, Le Danff C, Reboul M, Hilgert I, Rabreau M, Larrad ML, Pla M, Carosella ED, Rouas-Freiss N.
Hum Immunol. 2003 Mar;64(3):315-26.
PMID 12590976
HLA-G gene repression is reversed by demethylation.
Moreau P, Mouillot G, Rousseau P, Marcou C, Dausset J, Carosella ED.
Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1191-6. Epub 2003 Jan 27.
PMID 12552087
Secretion of sHLA-G molecules in malignancies.
Rebmann V, Regel J, Stolke D, Grosse-Wilde H.
Semin Cancer Biol. 2003 Oct;13(5):371-7.
PMID 14708717
Exosomes bearing HLA-G are released by melanoma cells.
Riteau B, Faure F, Menier C, Viel S, Carosella ED, Amigorena S, Rouas-Freiss N.
Hum Immunol. 2003 Nov;64(11):1064-72.
PMID 14602237
HLA-G in cancer: a way to turn off the immune system.
Rouas-Freiss N, Moreau P, Menier C, Carosella ED.
Semin Cancer Biol. 2003 Oct;13(5):325-36.
PMID 14708712
Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G.
Shiroishi M, Tsumoto K, Amano K, Shirakihara Y, Colonna M, Braud VM, Allan DS, Makadzange A, Rowland-Jones S, Willcox B, Jones EY, van der Merwe PA, Kumagai I, Maenaka K. REFERENCE Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8856-61. Epub 2003 Jul 9.
PMID 12853576
HLA-G is a potential tumor marker in malignant ascites.
Singer G, Rebmann V, Chen YC, Liu HT, Ali SZ, Reinsberg J, McMaster MT, Pfeiffer K, Chan DW, Wardelmann E, Grosse-Wilde H, Cheng CC, Kurman RJ, Shih IeM.
Clin Cancer Res. 2003 Oct 1;9(12):4460-4.
PMID 14555519
Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase.
Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ.
Nat Med. 2003 Oct;9(10):1269-74. Epub 2003 Sep 21.
PMID 14502282
The three Es of cancer immunoediting.
Dunn GP, Old LJ, Schreiber RD.
Annu Rev Immunol. 2004;22:329-60.
PMID 15032581
Analysis of HLA antigen expression in benign and malignant melanocytic lesions reveals that upregulation of HLA-G expression correlates with malignant transformation, high inflammatory infiltration and HLA-A1 genotype.
Ibrahim el C, Aractingi S, Allory Y, Borrini F, Dupuy A, Duvillard P, Carosella ED, Avril MF, Paul P.
Int J Cancer. 2004 Jan 10;108(2):243-50.
PMID 14639610
HLA-G1-expressing antigen-presenting cells induce immunosuppressive CD4+ T cells.
LeMaoult J, Krawice-Radanne I, Dausset J, Carosella ED.
Proc Natl Acad Sci U S A. 2004 May 4;101(18):7064-9. Epub 2004 Apr 21.
PMID 15103024
Erythroblasts secrete the nonclassical HLA-G molecule from primitive to definitive hematopoiesis.
Menier C, Rabreau M, Challier JC, Le Discorde M, Carosella ED, Rouas-Freiss N.
Blood. 2004 Nov 15;104(10):3153-60. Epub 2004 Jul 29.
PMID 15284117
Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes.
Munn DH, Sharma MD, Hou D, Baban B, Lee JR, Antonia SJ, Messina JL, Chandler P, Koni PA, Mellor AL.
J Clin Invest. 2004 Jul;114(2):280-90.
PMID 15254595
Soluble HLA-G generated by proteolytic shedding inhibits NK-mediated cell lysis.
Park GM, Lee S, Park B, Kim E, Shin J, Cho K, Ahn K.
Biochem Biophys Res Commun. 2004 Jan 16;313(3):606-11.
PMID 14697234
Protective immunity against disparate tumors is mediated by a nonpolymorphic MHC class I molecule.
Chiang EY, Stroynowski I.
J Immunol. 2005 May 1;174(9):5367-74.
PMID 15843534
HLA-G expression in effusions is a possible marker of tumor susceptibility to chemotherapy in ovarian carcinoma.
Davidson B, Elstrand MB, McMaster MT, Berner A, Kurman RJ, Risberg B, Trope CG, Shih IeM.
Gynecol Oncol. 2005 Jan;96(1):42-7.
PMID 15589578
The CD85J/leukocyte inhibitory receptor-1 distinguishes between conformed and beta 2-microglobulin-free HLA-G molecules.
Gonen-Gross T, Achdout H, Arnon TI, Gazit R, Stern N, Horejsi V, Goldman-Wohl D, Yagel S, Mandelboim O.
J Immunol. 2005 Oct 15;175(8):4866-74.
PMID 16210588
Linking two immuno-suppressive molecules: indoleamine 2,3 dioxygenase can modify HLA-G cell-surface expression.
Gonzalez-Hernandez A, LeMaoult J, Lopez A, Alegre E, Caumartin J, Le Rond S, Daouya M, Moreau P, Carosella ED.
Biol Reprod. 2005 Sep;73(3):571-8. Epub 2005 May 4.
PMID 15878889
NF-kappaB: linking inflammation and immunity to cancer development and progression.
Karin M, Greten FR.
Nat Rev Immunol. 2005 Oct;5(10):749-59.
PMID 16175180
Total soluble HLA class I and soluble HLA-G in multiple myeloma and monoclonal gammopathy of undetermined significance.
Leleu X, Le Friec G, Facon T, Amiot L, Fauchet R, Hennache B, Coiteux V, Yakoub-Agha I, Dubucquoi S, Avet-Loiseau H, Mathiot C, Bataille R, Mary JY; Intergroupe Francophone du Myelome.
Clin Cancer Res. 2005 Oct 15;11(20):7297-303.
PMID 16243800
HLA-G up-regulates ILT2, ILT3, ILT4, and KIR2DL4 in antigen presenting cells, NK cells, and T cells.
LeMaoult J, Zafaranloo K, Le Danff C, Carosella ED.
FASEB J. 2005 Apr;19(6):662-4. Epub 2005 Jan 24.
PMID 15670976
Indoleamine 2,3 dioxygenase and human leucocyte antigen-G inhibit the T-cell alloproliferative response through two independent pathways.
Le Rond S, Gonzalez A, Gonzalez AS, Carosella ED, Rouas-Freiss N.
Immunology. 2005 Nov;116(3):297-307.
PMID 16236119
HLA-G gene activation in tumor cells involves cis-acting epigenetic changes.
Mouillot G, Marcou C, Rousseau P, Rouas-Freiss N, Carosella ED, Moreau P.
Int J Cancer. 2005 Mar 1;113(6):928-36.
PMID 15514928
HLA-G expression is associated with an unfavorable outcome and immunodeficiency in chronic lymphocytic leukemia.
Nuckel H, Rebmann V, Durig J, Duhrsen U, Grosse-Wilde H.
Blood. 2005 Feb 15;105(4):1694-8. Epub 2004 Oct 5.
PMID 15466928
Report of the Wet Workshop for Quantification of Soluble HLA-G in Essen, 2004.
Rebmann V, Lemaoult J, Rouas-Freiss N, Carosella ED, Grosse-Wilde H.
Hum Immunol. 2005 Aug;66(8):853-63. Epub 2005 Jul 20.
PMID 16216668
Tolerization of dendritic cells by HLA-G.
Ristich V, Liang S, Zhang W, Wu J, Horuzsko A.
Eur J Immunol. 2005 Apr;35(4):1133-42.
PMID 15770701
Switch of HLA-G alternative splicing in a melanoma cell line causes loss of HLA-G1 expression and sensitivity to NK lysis.
Rouas-Freiss N, Bruel S, Menier C, Marcou C, Moreau P, Carosella ED.
Int J Cancer. 2005 Oct 20;117(1):114-22.
PMID 15880415
Induction of HLA-G expression in a melanoma cell line OCM-1A following the treatment with 5-aza-2'-deoxycytidine.
Yan WH, Lin AF, Chang CC, Ferrone S.
Cell Res. 2005 Jul;15(7):523-31.
PMID 16045815
Soluble HLA-G inhibits cell cycle progression in human alloreactive T lymphocytes.
Bahri R, Hirsch F, Josse A, Rouas-Freiss N, Bidere N, Vasquez A, Carosella ED, Charpentier B, Durrbach A.
J Immunol. 2006 Feb 1;176(3):1331-9.
PMID 16424159
The class I HLA repertoire of pancreatic islets comprises the nonclassical class Ib antigen HLA-G.
Cirulli V, Zalatan J, McMaster M, Prinsen R, Salomon DR, Ricordi C, Torbett BE, Meda P, Crisa L.
Diabetes. 2006 May;55(5):1214-22.
PMID 16644675
Soluble HLA-G1 inhibits angiogenesis through an apoptotic pathway and by direct binding to CD160 receptor expressed by endothelial cells.
Fons P, Chabot S, Cartwright JE, Lenfant F, L'Faqihi F, Giustiniani J, Herault JP, Gueguen G, Bono F, Savi P, Aguerre-Girr M, Fournel S, Malecaze F, Bensussan A, Plouet J, Le Bouteiller P.
Blood. 2006 Oct 15;108(8):2608-15. Epub 2006 Jun 29.
PMID 16809620
Soluble HLA-G molecules increase during acute leukemia, especially in subtypes affecting monocytic and lymphoid lineages.
Gros F, Sebti Y, de Guibert S, Branger B, Bernard M, Fauchet R, Amiot L.
Neoplasia. 2006 Mar;8(3):223-30.
PMID 16611416
HLA-G in human reproduction: aspects of genetics, function and pregnancy complications.
Hviid TV.
Hum Reprod Update. 2006 May-Jun;12(3):209-32. Epub 2005 Nov 9.
PMID 16280356
Evidence to support the role of HLA-G5 in allograft acceptance through induction of immunosuppressive/ regulatory T cells.
Le Rond S, Azema C, Krawice-Radanne I, Durrbach A, Guettier C, Carosella ED, Rouas-Freiss N.
J Immunol. 2006 Mar 1;176(5):3266-76.
PMID 16493088
Regulatory role of tryptophan degradation pathway in HLA-G expression by human monocyte-derived dendritic cells.
Lopez AS, Alegre E, LeMaoult J, Carosella E, Gonzalez A.
Mol Immunol. 2006 Jul;43(14):2151-60. Epub 2006 Feb 21.
PMID 16490253
Inhibition of term decidual NK cell cytotoxicity by soluble HLA-G1.
Poehlmann TG, Schaumann A, Busch S, Fitzgerald JS, Aguerre-Girr M, Le Bouteiller P, Schleussner E, Markert UR.
Am J Reprod Immunol. 2006 Nov-Dec;56(5-6):275-85.
PMID 17076671
Structural basis for recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2 (LILRB2/LIR2/ILT4/CD85d).
Shiroishi M, Kuroki K, Rasubala L, Tsumoto K, Kumagai I, Kurimoto E, Kato K, Kohda D, Maenaka K.
Proc Natl Acad Sci U S A. 2006a Oct 31;103(44):16412-7. Epub 2006 Oct 20.
PMID 17056715
Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer.
Shiroishi M, Kuroki K, Ose T, Rasubala L, Shiratori I, Arase H, Tsumoto K, Kumagai I, Kohda D, Maenaka K.
J Biol Chem. 2006b Apr 14;281(15):10439-47. Epub 2006 Feb 2.
PMID 16455647
Epigenetic regulation of MHC-II and CIITA genes.
Wright KL, Ting JP.
Trends Immunol. 2006 Sep;27(9):405-12. Epub 2006 Jul 25.
PMID 16870508
Increase in HLA-G1 proteolytic shedding by tumor cells: a regulatory pathway controlled by NF-kappaB inducers.
Zidi I, Guillard C, Marcou C, Krawice-Radanne I, Sangrouber D, Rouas-Freiss N, Carosella ED, Moreau P.
Cell Mol Life Sci. 2006 Nov;63(22):2669-81.
PMID 17072500
A homodimeric complex of HLA-G on normal trophoblast cells modulates antigen-presenting cells via LILRB1.
Apps R, Gardner L, Sharkey AM, Holmes N, Moffett A.
Eur J Immunol. 2007 Jul;37(7):1924-37.
PMID 17549736
Trogocytosis-based generation of suppressive NK cells.
Caumartin J, Favier B, Daouya M, Guillard C, Moreau P, Carosella ED, LeMaoult J.
EMBO J. 2007 Mar 7;26(5):1423-33. Epub 2007 Feb 22.
PMID 17318190
Research on HLA-G: an update.
Favier B, LeMaoult J, Rouas-Freiss N, Moreau P, Menier C, Carosella ED.
Tissue Antigens. 2007 Mar;69(3):207-11.
PMID 17493143
HLA-G expression is induced in Epstein-Barr virus-transformed B-cell lines by culture conditions.
Gazit E, Sherf M, Balbin E, Muratov A, Goldstein I, Loewenthal R.
Hum Immunol. 2007 Jun;68(6):463-8. Epub 2007 Mar 26.
PMID 17509445
Immune regulation by pretenders: cell-to-cell transfers of HLA-G make effector T cells act as regulatory cells.
LeMaoult J, Caumartin J, Daouya M, Favier B, Le Rond S, Gonzalez A, Carosella ED.
Blood. 2007 Mar 1;109(5):2040-8. Epub 2006 Oct 31.
PMID 17077329
Human neuroblastoma cells trigger an immunosuppressive program in monocytes by stimulating soluble HLA-G release.
Morandi F, Levreri I, Bocca P, Galleni B, Raffaghello L, Ferrone S, Prigione I, Pistoia V.
Cancer Res. 2007 Jul 1;67(13):6433-41.
PMID 17616704
Hypoxia modulates HLA-G gene expression in tumor cells.
Mouillot G, Marcou C, Zidi I, Guillard C, Sangrouber D, Carosella ED, Moreau P.
Hum Immunol. 2007 Apr;68(4):277-85. Epub 2006 Nov 27.
PMID 17400064
Indoleamine 2,3-dioxygenase and tumor-induced tolerance.
Munn DH, Mellor AL.
J Clin Invest. 2007 May;117(5):1147-54.
PMID 17476344
CD3+CD4low and CD3+CD8low are induced by HLA-G: novel human peripheral blood suppressor T-cell subsets involved in transplant acceptance.
Naji A, Le Rond S, Durrbach A, Krawice-Radanne I, Creput C, Daouya M, Caumartin J, LeMaoult J, Carosella ED, Rouas-Freiss N.
Blood. 2007 Dec 1;110(12):3936-48. Epub 2007 Sep 5.
PMID 17804694
Quantification and identification of soluble HLA-G isoforms.
Rebmann V, LeMaoult J, Rouas-Freiss N, Carosella ED, Grosse-Wilde H.
Tissue Antigens. 2007 Apr;69 Suppl 1:143-9.
PMID 17445190
Expression of tolerogenic HLA-G molecules in cancer prevents antitumor responses.
Rouas-Freiss N, Moreau P, Menier C, LeMaoult J, Carosella ED.
Semin Cancer Biol. 2007b Dec;17(6):413-21. Epub 2007 Jul 17.
PMID 17881247
Tolerogenic functions of human leukocyte antigen G: from pregnancy to organ and cell transplantation.
Rouas-Freiss N, Naji A, Durrbach A, Carosella ED.
Transplantation. 2007a Jul 15;84(1 Suppl):S21-5.
PMID 17632407
Tumor-released microvesicles as vehicles of immunosuppression.
Valenti R, Huber V, Iero M, Filipazzi P, Parmiani G, Rivoltini L.
Cancer Res. 2007 Apr 1;67(7):2912-5.
PMID 17409393
Human leukocyte antigen G expression: as a significant prognostic indicator for patients with colorectal cancer.
Ye SR, Yang H, Li K, Dong DD, Lin XM, Yie SM.
Mod Pathol. 2007 Mar;20(3):375-83. Epub 2007 Feb 2.
PMID 17277760
Expression of human leucocyte antigen G (HLA-G) is associated with prognosis in non-small cell lung cancer.
Yie SM, Yang H, Ye SR, Li K, Dong DD, Lin XM.
Lung Cancer. 2007a Nov;58(2):267-74. Epub 2007 Jul 30.
PMID 17673327
Expression of human leukocyte antigen G (HLA-G) correlates with poor prognosis in gastric carcinoma.
Yie SM, Yang H, Ye SR, Li K, Dong DD, Lin XM.
Ann Surg Oncol. 2007b Oct;14(10):2721-9. Epub 2007 Jun 13.
PMID 17564748
Expression of HLA-G is associated with prognosis in esophageal squamous cell carcinoma.
Yie SM, Yang H, Ye SR, Li K, Dong DD, Lin XM.
Am J Clin Pathol. 2007c Dec;128(6):1002-9.
PMID 18024326
HLA-G: from biology to clinical benefits.
Carosella ED, Moreau P, Lemaoult J, Rouas-Freiss N.
Trends Immunol. 2008 Mar;29(3):125-32. Epub 2008 Feb 4.
PMID 18249584
Role of HLA-G in innate immunity through direct activation of NF-kappaB in natural killer cells.
Guillard C, Zidi I, Marcou C, Menier C, Carosella ED, Moreau P.
Mol Immunol. 2008 Jan;45(2):419-27. Epub 2007 Aug 1.
PMID 17675239
Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape.
Katz JB, Muller AJ, Prendergast GC.
Immunol Rev. 2008 Apr;222:206-21.
PMID 18364004
HLA-G turns off erythropoietin receptor signaling through JAK2 and JAK2 V617F dephosphorylation: clinical relevance in polycythemia vera.
Menier C, Guillard C, Cassinat B, Carosella ED, Rouas-Freiss N.
Leukemia. 2008 Mar;22(3):578-84. Epub 2007 Dec 6.
PMID 18059484
Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells.
Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L, Borg C, Saas P, Tiberghien P, Rouas-Freiss N, Carosella ED, Deschaseaux F.
Stem Cells. 2008 Jan;26(1):212-22. Epub 2007 Oct 11.
PMID 17932417
Written2008-07Catherine Menier, Nathalie Rouas-Freiss, Edgardo D Carosella
de Recherche en Hemato-Immunologie, Hopital Saint Louis, CEA - Batiment Lailler, 1, av. Claude Vellefaux, 75475 Paris Cedex 10 - France


This paper should be referenced as such :
Menier, C ; Rouas-Freiss, N ; Carosella, ED. The HLA-G non classical MHC class I molecule is expressed in cancer with poor prognosis
Implications in tumour escape from immune system and clinical applications
Atlas Genet Cytogenet Oncol Haematol. 2009;13(7):531-542.
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