Expression of functional soluble human leucocyte antigen-G molecules in lymphoproliferative disorders

UPRES Immunologie Hématologie, Université de Rennes 1, Rennes, France.
British Journal of Haematology (Impact Factor: 4.71). 08/2007; 138(2):202-12. DOI: 10.1111/j.1365-2141.2007.06647.x
Source: PubMed


Membrane-bound and soluble human leucocyte antigen-G (sHLA-G) molecules display immunotolerant properties favouring tumour cell escape from immune surveillance. sHLA-G molecules have been detected in several tumour pathologies; this study aimed to evaluate sHLA-G expression in lymphoproliferative disorders. sHLA-G plasma level was significantly increased in 110 of 178 newly diagnosed lymphoid proliferations cases i.e. 59% of chronic lymphocytic leukaemia, 65% of B non-Hodgkin lymphomas (NHL) and 58% of T-NHL. To assess the mechanisms involved in this secretion, the differential effect of cytokines was tested in in vitro cultures of NHL cells. A significant induction of sHLA-G level was shown in T-NHL in contrast with B-NHL and normal equivalent cells, after cytokine stimulation with (i) interferongamma (IFNgamma), interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor, (ii) IL-10 and (iii) transforming growth factor beta. An impact of microenvironment on sHLA-G expression was found in B-NHL as shown by the in vitro effect of addition of normal monocytes. Finally, a functional effect of sHLA-G molecules purified from pathologic plasma was demonstrated by their strong capacity to inhibit T-cell proliferation at concentrations currently observed during these disorders. These results suggest that functional sHLA-G molecules are upregulated in lymphoproliferative disorders which can support their potential immunomodulatory role during this pathology.

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Available from: Amélie Huynh Le Maux, Oct 28, 2015
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    • "This inhibitory effect is mediated by direct binding of both soluble and membranebound HLA-G to inhibitory receptors, such as the immunoglobulin-like transcript LILRB1 (ILT-2, CD85J), which is expressed by both lymphoid and myeloid cells, LILRB2 (ILT-4; CD85D) that is only expressed by myeloid cells, and KIR2DL4 (killer cell immunoglobulin-like receptor, CD158d) detected solely on NK cells (LeMaoult et al., 2003; Carosella et al., 2008; Loustau et al., 2013). It has also been reported that higher plasma levels of soluble HLA-G (sHLA-G) are observed in patients with lymphoproliferative neoplasms, such as chronic lymphocytic leukemia (CLL), B-cell NHL, and T-cell NHL, when compared with controls (Nuckel et al., 2005; Rebmann et al., 2007; Sebti et al., 2007; Giannopoulos et al., 2008). This indicates that increased HLA-G expression promotes immune escape mechanisms that contribute to the tolerogenic status of the immune system leading to tumor cells' survival (Carosella et al., 2008). "
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    ABSTRACT: The role of HLA-G is extensively studied in cancer due to its inhibition of the immune response. Several polymorphisms in the HLA-G gene have been reported to significantly affect its expression. We, therefore, investigated whether functionally relevant HLA-G polymorphisms, HLA-G-725C/G/T, and HLA-G 14-base pair, have any influence on the susceptibility to diffuse large B-cell lymphoma (DLBCL) and its clinical course. The polymorphisms were genotyped in 207 previously untreated patients with DLBCL and 150 unrelated controls. A significant difference in genotype distribution of HLA-G polymorphic genotypes between the patients and controls was found. The frequencies of the HLA-G−725GG or the HLA-G−725GC genotype were lower, and those of the HLA-G ins/ins genotype were higher in the patients compared with the controls. Patients carrying the HLA-G-725CC genotype presented a higher probability of overall survival (OS) than subjects with other genotype combinations of HLA-G-725C/G/T (P = 0.003). The homozygous HLA-G del/del had a lower probability of OS than subjects carrying the HLA-G deletion/insertion (del/ins) or the HLA-G ins/ins genotype (P = 0.009). Two HLA-G genotype-based risk groups were defined according to the genotype distribution. The high-risk (HR) group presented a shorter OS than low-risk (LR) patients (P = 0.001). In a multivariate analysis adjusted for International Prognostic Index (IPI) factors, both the intermediate high/high IPI-risk group (P < 0.0001) and the HR genotype group (P = 0.004) independently increased the risk of death. This is the first study indicating an important role of HLA-G polymorphisms for the clinical course of DLBCL. The potential influence of HLA-G polymorphisms on the susceptibility to DLBCL thus deserves further study. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Mar 2015 · Genes Chromosomes and Cancer
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    • "Whereas HLA-G expression and its clinical significance in solid tumors have been extensively investigated showing that HLA-G expression in such tumor cells has unfavorable outcome or prognosis [34]; only a few data are available for the HLA-G expression and its clinical significance in liquid malignancies. In this regard, enhanced sHLA-G (i.e., HLA-G5 and shed HLA-G1) plasma levels have been described in B cell malignancies, such as multiple myeloma, non-Hodgkin B-lymphoma, and B-CLL [35, 36]. However, no clear correlation was established between HLA-G and unfavorable clinical outcome in hematological malignancies. "
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    ABSTRACT: We here review the current data on the role of HLA-G in cancer based on recent findings of an unexpected antitumor activity of HLA-G in hematological malignancies. For the past decade, HLA-G has been described as a tumor-escape mechanism favoring cancer progression, and blocking strategies have been proposed to counteract it. Aside from these numerous studies on solid tumors, recent data showed that HLA-G inhibits the proliferation of malignant B cells due to the interaction between HLA-G and its receptor ILT2, which mediates negative signaling on B cell proliferation. These results led to the conjecture that, according to the malignant cell type, HLA-G should be blocked or conversely induced to counteract tumor progression. In this context, we will here present (i) the dual role of HLA-G in solid and liquid tumors with special emphasis on (ii) the HLA-G active structures and their related ILT2 and ILT4 receptors and (iii) the current knowledge on regulatory mechanisms of HLA-G expression in tumors.
    Full-text · Article · Mar 2014 · Journal of Immunology Research
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