Therapeutic potential of Galectin-9 in human disease (original) (raw)
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Galectin-9 Triggers Neutrophil-Mediated Anticancer Immunity
Biomedicines
In earlier studies, galectin-9 (Gal-9) was identified as a multifaceted player in both adaptive and innate immunity. Further, Gal-9 had direct cytotoxic and tumor-selective activity towards cancer cell lines of various origins. In the current study, we identified that treatment with Gal-9 triggered pronounced membrane alterations in cancer cells. Specifically, phosphatidyl serine (PS) was rapidly externalized, and the anti-phagocytic regulator, CD47, was downregulated within minutes. In line with this, treatment of mixed neutrophil/tumor cell cultures with Gal-9 triggered trogocytosis and augmented antibody-dependent cellular phagocytosis of cancer cells. Interestingly, this pro-trogocytic effect was also due to the Gal-9-mediated activation of neutrophils with upregulation of adhesion markers and mobilization of gelatinase, secretory, and specific granules. These activation events were accompanied by a decrease in cancer cell adhesion in mixed cultures of leukocytes and cancer cell...
Journal of Biological Chemistry, 2015
Background: Signals triggered by galectin-9 in human T cells are poorly understood. Results: Impairment of Lck or T cell receptor-CD3 complex inhibits calcium mobilization and cytokine production but not apoptosis induced by galectin-9. Conclusion: Galectin-9 triggers two independent pathways in T cells, with one mimicking the antigen-specific activation. Significance: We discovered a novel mechanism involved in galectin-9 immunomodulatory effects. Galectin-9 (gal-9) is a multifunctional -galactoside-binding lectin, frequently released in the extracellular medium, where it acts as a pleiotropic immune modulator. Despite its overall immunosuppressive effects, a recent study has reported bimodal action of gal-9 on human resting blood T cells with apoptosis occurring in the majority of them, followed by a wave of activation and expansion of Th1 cells in the surviving population. Our knowledge of the signaling events triggered by exogenous gal-9 in T cells remains limited. One of these events is cytosolic calcium (Ca 2؉) release reported in some murine and human T cells. The aim of this study was to investigate the contribution of Ca 2؉ mobilization to apoptotic and nonapoptotic effects of exogenous gal-9 in human T cells. We found that the T cell receptor (TCR)-CD3 complex and the Lck kinase were required for Ca 2؉ mobilization but not for apoptosis induction in Jurkat cells. These data were confirmed in human CD4 ؉ T cells from peripheral blood as follows: a specific Lck chemical inhibitor abrogated Ca 2؉ mobilization but not apoptosis induction. Moreover, Lck activity was also required for the production of Th1-type cytokines, i.e. interleukin-2 and interferon-␥, which resulted from gal-9 stimulation in peripheral CD4 ؉ T cells. These findings indicate that gal-9 acts on T cells by two distinct pathways as follows: one mimicking antigen-specific activation of the TCR with a mandatory contribution of proximal elements of the TCR complex, especially Lck, and another resulting in apoptosis that is independent of this complex. * This work was supported in part by Institut National du Cancer Grant INCa-DHOS 2010 and the Ligue Nationale Contre le Cancer (Comité du Val de Marne). The authors declare that they have no conflicts of interest with the contents of this article. 1 Supported by a fellowship from the Association Nationale Recherche-Technologie. 2 Supported by a fellowship from Association pour la Recherche Contre le Cancer.
International Journal of Molecular Sciences
Galectins are a family of ß-galactoside-binding proteins that play a variety of roles in normal physiology. In cancer, their expression levels are typically elevated and often associated with poor prognosis. They are known to fuel a variety of cancer progression pathways through their glycan-binding interactions with cancer, stromal, and immune cell surfaces. Of the 15 galectins in mammals, galectin (Gal)-1, -3, and -9 are particularly notable for their critical roles in tumor immune escape. While these galectins play integral roles in promoting cancer progression, they are also instrumental in regulating the survival, differentiation, and function of anti-tumor T cells that compromise anti-tumor immunity and weaken novel immunotherapies. To this end, there has been a surge in the development of new strategies to inhibit their pro-malignancy characteristics, particularly in reversing tumor immunosuppression through galectin–glycan ligand-targeting methods. This review examines some ...
Biomolecules
Galectins are small proteins with pleiotropic functions, which depend on both their lectin (glycan recognition) and non-lectin (recognition of other biomolecules besides glycans) interactions. Currently, 15 members of this family have been described in mammals, each with its structural and ligand recognition particularities. The galectin/ligand interaction translates into a plethora of biological functions that are particular for each cell/tissue type. In this sense, the cells of the immune system are highly sensitive to the action of these small and essential proteins. While galectins play central roles in tumor progression, they are also excellent negative regulators (checkpoints) of the immune cell functions, participating in the creation of a microenvironment that promotes tumor escape. This review aims to give an updated view on how galectins control the tumor’s immune attack depending on the tumor microenvironment, because determining which galectins are essential and the role...
The roles of Galectin-3 in autoimmunity and tumor progression
Immunologic Research, 2012
Galectin-3, a unique chimera-type member of the b-galactoside-binding soluble lectin family, is widely expressed in numerous cells. Here, we discuss the role of Galectin-3 in T-cell-mediated inflammatory (auto) immunity and tumor rejection by using Galectin-3-deficient mice and four disease models of human pathology: experimental autoimmune encephalomyelitis (EAE), Con-A-induced hepatitis, multiple low-dose streptozotocin-induced diabetes (MLD-STZ diabetes) and metastatic melanoma. We present evidence which suggest that Galectin-3 plays an important pro-inflammatory role in Con-A-induced hepatitis by promoting the activation of T lymphocytes, NKT cells and DCs, cytokine secretion, prevention of M2 macrophage polarization and apoptosis of mononuclear cells, and it leads to severe liver injury. In addition, experiments in Galectin-3-''knock-out'' mice indicate that Galectin-3 is also involved in immune-mediated b-cell damage and is required for diabetogenesis in MLD-STZ model by promoting the expression of IFN-gamma, TNF-alpha, IL-17 and iNOS in immune and accessory effector cells. Next, our data demonstrated that Galectin-3 plays an important disease-exacerbating role in EAE through its multifunctional roles in preventing cell apoptosis and increasing IL-17 and IFN-gamma synthesis, but decreasing IL-10 production. Finally, based on our findings, we postulated that expression of Galectin-3 in the host may also facilitate melanoma metastasis by affecting tumor cell adhesion and modulating antimelanoma immune response, in particular innate antitumor immunity. Taken together, we discuss the evidence of proinflammatory and antitumor activities of Galectin-3 and suggest that Galectin-3 may be an important therapeutic target. Keywords Galectin-3 Á Con-A-induced hepatitis Á Multiple low-dose streptozotocin-induced diabetes Á Experimental autoimmune encephalomyelitis Á Melanoma metastasis
Galectin-9 Activates and Expands Human T-Helper 1 Cells
PLoS ONE, 2013
Galectin-9 (Gal-9) is known for induction of apoptosis in IFN-c and IL-17 producing T-cells and amelioration of autoimmunity in murine models. On the other hand, Gal-9 induced IFN-c positive T-cells in a sarcoma mouse model and in food allergy, suggesting that Gal-9 can have diametric effects on T-cell immunity. Here, we aimed to delineate the immunomodulatory effect of Gal-9 on human resting and ex vivo activated peripheral blood lymphocytes. Treatment of resting lymphocytes with low concentrations of Gal-9 (5-30 nM) induced apoptosis in ,60% of T-cells after 1 day, but activated the surviving Tcells. These viable T-cells started to expand after 4 days with up to 6 cell divisions by day 7 and an associated shift from naïve towards central memory and IFN-c producing phenotype. In the presence of T-cell activation signals (anti-CD3/IL-2) Gal-9 did not induce T-cell expansion, but shifted the CD4/CD8 balance towards a CD4-dominated T-cell response. Thus, Gal-9 activates resting T-cells in the absence of typical T-cell activating signals and promotes their transition to a T H1/C1 phenotype. In the presence of T-cell activating signals T-cell immunity is directed towards a CD4-driven response by Gal-9. Thus, Gal-9 may specifically enhance reactive immunological memory.
Science Reviews - from the end of the world
Endogenous lectins play key roles in cell homeostasis by decoding the information encrypted in glycans present on the cell surface or extracellular matrix. Galectins, a family of soluble lectins, have emerged as central regulators of innate and adaptive immune responses. In this article, we review seminal work demonstrating the immunoregulatory roles of Galectin-1 (Gal-1), a proto-type member of the galectin family, and highlight central mechanisms that control its functions in cancer and autoimmune inflammation. Understanding the cellular pathways that control Gal-1 expression and function in tumor and inflammatory microenvironments will set the bases for the design of rational therapies based on positive or negative modulation of this endogenous lectin in cancer and autoimmune diseases.
Cancer Therapy Due to Apoptosis: Galectin-9
Dysregulation of apoptosis is a major hallmark in cancer biology that might equip tumors with a higher malignant potential and chemoresistance. The anti-cancer activities of lectin, defined as a carbohydrate-binding protein that is not an enzyme or antibody, have been investigated for over a century. Recently, galectin-9, which has two distinct carbohydrate recognition domains connected by a linker peptide, was noted to induce apoptosis in thymocytes and immune cells. The apoptosis of these cells contributes to the development and regulation of acquired immunity. Furthermore, human recombinant galectin-9, hG9NC (null), which lacks an entire region of the linker peptide, was designed to resist proteolysis. The hG9NC (null) has demonstrated anti-cancer activities, including inducing apoptosis in hematological, dermatological and gastrointestinal malignancies. In this review, the molecular characteristics, history and apoptosis-inducing potential of galectin-9 are described.
Cancer Research, 2010
Human CD8 + tumor-infiltrating T lymphocytes (TIL), in contrast with CD8 + blood cells, show impaired IFN-γ secretion on ex vivo restimulation. We have attributed the impaired IFN-γ secretion to a decreased mobility of T-cell receptors on trapping in a lattice of glycoproteins clustered by extracellular galectin-3. Indeed, we have previously shown that treatment with N-acetyllactosamine, a galectin ligand, restored this secretion. We strengthened this hypothesis here by showing that CD8 + TIL treated with an anti-galectin-3 antibody had an increased IFN-γ secretion. Moreover, we found that GCS-100, a polysaccharide in clinical development, detached galectin-3 from TIL and boosted cytotoxicity and secretion of different cytokines. Importantly, we observed that not only CD8 + TIL but also CD4 + TIL treated with GCS-100 secreted more IFN-γ on ex vivo restimulation. In tumor-bearing mice vaccinated with a tumor antigen, injections of GCS-100 led to tumor rejection in half of the mice, whereas all control mice died. In nonvaccinated mice, GCS-100 had no effect by itself. These results suggest that a combination of galectin-3 ligands and therapeutic vaccination may induce more tumor regressions in cancer patients than vaccination alone. Cancer Res; 70(19); 7476-88. ©2010 AACR.
Journal for ImmunoTherapy of Cancer
BackgroundGalectin-9 is a member of the family of lectin proteins and crucially regulates human immune responses, particularly because of its ability to suppress the anticancer activities of T lymphocytes and natural killer cells. Recent evidence demonstrated that galectin-9 is highly expressed in a wide range of human malignancies including the most aggressive tumors, such as high-grade glioblastomas and pancreatic ductal adenocarcinomas, as well as common malignancies such as breast, lung and colorectal cancers. However, solid tumor cells at rest are known to secrete either very low amounts of galectin-9 or, in most of the cases, do not secrete it at all. Our aims were to elucidate whether T cells can induce galectin-9 secretion in human cancer cells derived from solid malignant tumors and whether this soluble form displays higher systemic immunosuppressive activity compared with the cell surface-based protein.MethodsA wide range of human cancer cell lines derived from solid tumou...