HLA-G neo-expression modifies genetic programs governing tumor cell lines.

The development of immunotherapies has proved to be clinically encouraging to re-establish the immune function modified by the expression of immune inhibitory molecules in tumors. However, there are still patients with poor survival rates following treatment. The elucidation of molecular mechanisms triggered by the neo-expression of particular IC in tumors would constitute a major step toward better understanding tumor evolution and would help to design future clinical protocols.

Co-Transplantation of Barcoded Lymphoid-Primed Multipotent (LMPP) and Common Lymphocyte (CLP) Progenitors Reveals a Major Contribution of LMPP to the Lymphoid Lineage.

T cells have the potential to maintain immunological memory and self-tolerance by recognizing antigens from pathogens or tumors. In pathological situations, failure to generate de novo T cells causes immunodeficiency resulting in acute infections and complications. Hematopoietic stem cells (HSC) transplantation constitutes a valuable option to restore proper immune function.

The HLA-G immune checkpoint: a new immuno-stimulatory role for the α1-domain-deleted isoform.

The heterogeneity of cancer cells, in part maintained via the expression of multiple isoforms, introduces significant challenges in designing effective therapeutic approaches. In this regard, isoforms of the immune checkpoint HLA-G have been found in most of the tumors analyzed, such as ccRCC, the most common human renal malignancy. In particular, HLA-G∆α1, which is the only HLA-G isoform described that lacks the α1 extracellular domain, has been newly identified in ccRCC and now here in trophoblasts.

HLA-G gene editing in tumor cell lines as a novel alternative in cancer immunotherapy.

Cancer immunotherapies based mainly on the blockade of immune-checkpoint (IC) molecules by anti-IC antibodies offer new alternatives for treatment in oncological diseases. However, a considerable proportion of patients remain unresponsive to them. Hence, the development of novel clinical immunotherapeutic approaches and/or targets are crucial.

Comprehensive landscape of immune-checkpoints uncovered in clear cell renal cell carcinoma reveals new and emerging therapeutic targets.

Clear cell renal cell carcinoma (ccRCC) constitutes the most common renal cell carcinoma subtype and has long been recognized as an immunogenic cancer. As such, significant attention has been directed toward optimizing immune-checkpoints (IC)-based therapies. Despite proven benefits, a substantial number of patients remain unresponsive to treatment, suggesting that yet unreported, immunosuppressive mechanisms coexist within tumors and their microenvironment.

Human Hepatocytes and Differentiated Adult-Derived Human Liver Stem/Progenitor Cells Display Immunosuppressive Properties Mediated, at Least in Part, through the Nonclassical HLA Class I Molecule HLA-G.

One of the main challenges in liver cell therapy (LCT) is the induction of a tolerogenic microenvironment to promote graft acceptance in the recipient. Little is known about the immunomodulatory potential of the hepatic cells used in liver cell therapy. In this work, we wanted to evaluate the immunosuppressive properties of human hepatocytes and adult-derived human liver stem/progenitor cells (ADHLSCs), as well as the potential involvement of the immunomodulatory molecule HLA-G.

Expression and differential regulation of HLA-G isoforms in the retinal pigment epithelial cell line, ARPE-19.

The purpose of this study was to examine if HLA-G is expressed in the retinal pigment epithelium (RPE) cells of the eye. The RPE comprises the outer most layer of the retina and as such defines the interface to the blood and contributes to the immune privilege in the posterior part of the eye. One way the RPE might be regulating the immune system could be by expressing the non-classical human leukocyte antigen (HLA) molecule, HLA-G.

Trogocytic intercellular membrane exchanges among hematological tumors.

Trogocytosis is the transfer of plasma membrane fragments and the molecules they contain between one donor and one acceptor/acquirer cell. Through trogocytosis, acceptor cells temporarily display and use cell-surface molecules they do not express themselves, but borrow from other cells. Here, we investigated whether liquid tumors possessed a trogocytic capability, if immune escape molecules could be acquired by tumor cells, transferred between cells of the same tumor, and if this could benefit the tumor as a whole.

Synthetic HLA-G proteins for therapeutic use in transplantation.

The human leukocyte antigen (HLA)-G is a tolerogenic molecule, whose expression by allografts is associated with better acceptance. An increasing interest in producing HLA-G as a clinical-grade molecule for therapy use is impaired by its complexity and limited stability. Our purpose was to engineer simpler and more stable HLA-G-derived molecules than the full-length HLA-G trimolecular complex that are also tolerogenic, functional as soluble molecules, and compatible with good manufacturing practice (GMP) production conditions.

Multimeric structures of HLA-G isoforms function through differential binding to LILRB receptors.

The non-classical Human leukocyte antigen G (HLA-G) differs from classical HLA class I molecules by its low genetic diversity, a tissue-restricted expression, the existence of seven isoforms, and immuno-inhibitory functions. Most of the known functions of HLA-G concern the membrane-bound HLA-G1 and soluble HLA-G5 isoforms, which present the typical structure of classical HLA class I molecule: a heavy chain of three globular domains α1-α2-α3 non-covalently bound to β-2-microglobulin (B2M) and a peptide. Very little is known of the structural features and functions of other HLA-G isoforms or structural conformations other than B2M-associated HLA-G1 and HLA-G5.

Tolerogenic function of dimeric forms of HLA-G recombinant proteins: a comparative study in vivo.

HLA-G is a natural tolerogenic molecule involved in the best example of tolerance to foreign tissues there is: the maternal-fetal tolerance. The further involvement of HLA-G in the tolerance of allogeneic transplants has also been demonstrated and some of its mechanisms of action have been elucidated. For these reasons, therapeutic HLA-G molecules for tolerance induction in transplantation are actively investigated.

Proper regrafting of Ig-like transcript 2 after trogocytosis allows a functional cell-cell transfer of sensitivity.

The acquisition by T cells of exogenous ligands originally expressed by APC has been already described. However, reports essentially focused on the outward signaling of acquired ligands and their effects on surroundings cells. We investigated the function of transferred receptors (not ligands) on the T cells that acquired them (not on cells they interact with).

Membrane redistributions through multi-intercellular exchanges and serial trogocytosis.

Trogocytosis is a rapid transfer between cells of membranes and associated proteins. Trogocytic exchanges have been investigated between different cell types, mainly in two-cell systems, involving one donor and one acceptor cell type. Here, we studied trogocytosis in a more complex system, involving not only several immune cell subsets but also multiple tumor cells.

Different functional outcomes of intercellular membrane transfers to monocytes and T cells.

Trogocytosis is the uptake of membranes from one cell by another. Trogocytosis has been demonstrated for monocytes, B cells, T cells, and NK cells. The acquisition of the tolerogenic molecule HLA-G by T cells and NK cells makes them behave as regulatory cells.

CD3+CD4low and CD3+CD8low are induced by HLA-G: novel human peripheral blood suppressor T-cell subsets involved in transplant acceptance.

HLA-G is a tolerogenic molecule whose detection in sera and within allografted tissues is associated with better graft acceptance. HLA-G mediates T-cell differentiation into suppressor cells, which are thought to promote tolerance. Here, we investigated such T cells phenotypically and functionally and assessed their clinical relevance in the peripheral blood of patients who have undergone transplantation.

Trogocytosis-based generation of suppressive NK cells.

Trogocytosis is a fast uptake of membranes and associated molecules from one cell by another. Trogocytosis between natural killer (NK) cells and tumors is already described, but the functional relevance of NK-tumor targets material exchange is unclear. We investigated whether the immunosuppressive molecule HLA-G that is commonly expressed by tumors in vivo and known to block NK cytolytic function, could be transferred from tumor cells to NK cells, and if this transfer had functional consequences.

Immune regulation by pretenders: cell-to-cell transfers of HLA-G make effector T cells act as regulatory cells.

Trogocytosis is the uptake of membrane fragments from one cell by another and has been described for immune cells in mice and humans. Functional consequences of trogocytosis are emerging, but a dramatic immune function has still to be associated with it. Here we show that some resting, and most activated, CD4+ and CD8+ T cells acquire immunosuppressive HLA-G1 from antigen-presenting cells (APCs) in a few minutes.

Linking two immuno-suppressive molecules: indoleamine 2,3 dioxygenase can modify HLA-G cell-surface expression.

Nonclassical human leukocyte antigen (HLA) class I molecule HLA-G and indoleamine 2,3 dioxygenase (INDO) in humans and mice, respectively, have been shown to play crucial immunosuppressive roles in fetal-maternal tolerance. HLA-G inhibits natural killer and T cell function by high-affinity interaction with inhibitory receptors, and INDO acts by depleting the surrounding microenvironment of the essential amino acid tryptophan, thus inhibiting T cell proliferation. We investigated whether HLA-G expression and INDO function were linked.