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: 4.94). 08/2007; 138(2):202-12. DOI: 10.1111/j.1365-2141.2007.06647.x
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Human leukocyte antigen-G (HLA-G) is a low polymorphic nonclassical HLA-I molecule restrictively expressed and with suppressive functions. HLA-G gene products are quite complex, with seven HLA-G isoforms, four membrane bound, and other three soluble isoforms that can suffer different posttranslational modifications or even complex formations. In addition, HLA-G has been described included in exosomes. In this review we will focus on HLA-G biochemistry with special emphasis to the mechanisms that regulate its expression and how the protein modifications affect the quantification in biological fluids.
    Journal of immunology research. 01/2014; 2014:657625.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human Leukocyte Antigen-G (HLA-G) expression by tumors has been evidenced in numerous malignancies in association with poor prognosis and resistance to immunotherapy in humans. Particularly, soluble form of HLA-G was measured at high concentrations in malignant effusions and plasma from cancer patients and inhibits anti-tumor immune cells in vitro through interaction with immunoglobulin-like transcript (ILT) receptors. Nevertheless, in vivo study demonstrating that HLA-G secretion by tumor cells allows their escape from immunosurveillance remained to be established. Despite non-described murine homolog, direct functional interaction of HLA-G with murine paired immunoglobulin-like receptor (PIR)-B, ortholog of human ILT receptors, enables to investigate its role in vivo. Immunocompetent mice were injected either with syngeneic tumor cells co-expressing HLA-G5, the main soluble HLA-G isoform, and the conformation stabilizer human β2-microglubulin (hβ2m), or with hβ2m(+) HLA-G5(-) tumor cells. hβ2m expressed at both tumor cell surface acted as a tumor antigen triggering a specific humoral response. Interestingly, while hβ2m(+) HLA-G5(-) tumors were rejected, secreted HLA-G5 provided hβ2m(+) HLA-G5(+) tumors a protection against hβ2m-elicited immune rejection, enabling such immunogenic tumors to grow similarly to a poorly immunogenic tumor. HLA-G5 tumor expression was associated with local and peripheral immunosuppression, characterized by dampened anti-hβ2m B cell response, quantitative and functional T and B cell defects, accumulation of myeloid-derived suppressor cells able to inhibit T cell proliferation, and reduced T and B cell tumor-infiltrate. Our study provides the first in vivo proof that soluble HLA-G counteracts tumor rejection and reinforces the importance to consider HLA-G as a promising target to optimize current cancer immunotherapies. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 03/2014; · 6.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Colorectal cancer (CRC) is one of the most diffuse cancers worldwide and is still a clinical burden. Increasing evidences associate CRC clinical outcome to immune contexture represented by adaptive immune cells. Their type, density and location are summarized in the Immune Score that has been shown to improve prognostic prediction of CRC patients. The non-classical MHC class I human leukocyte antigen-G (HLA-G), is a crucial tumor-driven immune escape molecule involved in immune tolerance. HLA-G and soluble counterparts are able to exert inhibitory functions by direct interactions with inhibitory receptors present on both innate cells such as natural killer cells, and adaptive immune cells as cytotoxic T and B lymphocytes. HLA-G may play a prominent role in CRC strategies to avoid host immunosurveillance. This review highlights the current knowledge on HLA-G contribution in CRC, in related inflammatory diseases and in other type of cancers and disorders. HLA-G genetic setting (specific haplotypes, genotypes and alleles frequencies) and association with circulating/soluble profiles was highlighted. HLA G prognostic and predictive value in CRC was investigated in order to define a novel prognostic immune biomarker in CRC.
    World Journal of Gastroenterology 04/2014; 20(14):3778-3794. · 2.55 Impact Factor