Glycan-Lectin Interactions as Novel Immunosuppression Drivers in Glioblastoma (original) (raw)
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Galectins as Emerging Glyco-Checkpoints and Therapeutic Targets in Glioblastoma
International Journal of Molecular Sciences, 2021
Despite recent advances in diagnosis and treatment, glioblastoma (GBM) represents the most common and aggressive brain tumor in the adult population, urging identification of new rational therapeutic targets. Galectins, a family of glycan-binding proteins, are highly expressed in the tumor microenvironment (TME) and delineate prognosis and clinical outcome in patients with GBM. These endogenous lectins play key roles in different hallmarks of cancer by modulating tumor cell proliferation, oncogenic signaling, migration, vascularization and immunity. Additionally, they have emerged as mediators of resistance to different anticancer treatments, including chemotherapy, radiotherapy, immunotherapy, and antiangiogenic therapy. Particularly in GBM, galectins control tumor cell transformation and proliferation, reprogram tumor cell migration and invasion, promote vascularization, modulate cell death pathways, and shape the tumor-immune landscape by targeting myeloid, natural killer (NK), a...
Regulatory Circuits Mediated by Lectin-Glycan Interactions in Autoimmunity and Cancer
Immunity, 2012
Numerous regulatory programs have been identified that contribute to the restoration of homeostasis at the conclusion of immune responses and to safeguarding against the detrimental effects of chronic inflammation and autoimmune pathology. Malignant cells may usurp these pathways to create immunosuppressive networks that thwart antitumor responses. Herein we review the role of endogenous lectins (C-type lectins, siglecs, and galectins) and specific N-and O-glycans generated by the coordinated action of glycosyltransferases and glycosidases that together promote regulatory signals that control immune cell homeostasis. We also discuss the mechanisms by which glycan-dependent regulatory programs integrate into canonical circuits that amplify or silence immune responses related to autoimmunity and neoplastic disease. these high-ordered supramolecular complexes need to be further characterized at the cellular level by both in vitro and in vivo visualization approaches. Nevertheless, multivalent lectin-glycan complexes have been proposed to serve as scaffolds for organizing plasma membrane domains, which in turn modulate the signaling threshold of relevant surface glycoproteins including the T cell receptor (TCR), B cell receptor (BCR), and specific cytokine receptors (Dennis et al., 2009). We focus here on three lectin families that are involved in glycan recognition and signaling in the immune system: C-type lectins, siglecs, and galectins (Figure 1). C-type lectin receptors (CLRs) are a heterogeneous family of Ca 2+-dependent glycan-binding proteins that can be divided into two categories on the basis of an amino acid motif involved in glycan recognition and coordination of the Ca 2+ ion. Most CLRs are glycan-binding receptors that contain one or more carbohydrate-recognition domains (CRDs) and are expressed on the surface of numerous cell types including macrophages and dendritic cells (DCs). CLRs that contain an EPN (Glu-Pro-Asn) amino acid motif typically have specificity for mannose-or fucose-containing glycans (Lewis a,b,x,y). These include the DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), mannose receptor (MR), and langerin. In contrast, galactose-specific CLRs, such as macrophage galactose lectin (MGL), contain a QPD (Gln-Pro-Asp) sequence and recognize N-acetylgalactosamine (Gal-NAc)-terminated glycans (Drickamer, 1999). However, CLRs displaying Ca 2+-independent glycan recognition also exist, including Dectin-1, which specifically recognizes b-glucan
Frontiers in Immunology
Many tumors display alterations in the biosynthetic pathways of glycosylation, resulting in increased expression of specific tumor-associated glycan structures. Expression of these altered glycan structures is associated with metastasis and poor prognosis. Antigen presenting cells can recognize tumor-associated glycan structures, including the truncated O-glycan Tn antigen, via specific glycan receptors. Tn antigen-mediated activation of the C-type lectin MGL on dendritic cells induces regulatory T cells via the enhanced secretion of IL-10. Although these findings indicate that MGL engagement by glycan ligands can modulate immune responses, the impact of MGL ligation on dendritic cells is still not completely understood. Therefore, we employed RNA sequencing, GO term enrichment and pathway analysis on human monocyte-derived dendritic cells stimulated with two different MGL glycan ligands. Our analyses revealed a reduced expression of genes coding for key enzymes involved in the glycolysis pathway, TCA cycle, and oxidative phosphorylation. In concordance with this, extracellular flux analysis confirmed the decrease in glycolytic activity upon MGL triggering in human dendritic cells. To our knowledge, we are the first to report a diminished glycolytic activity of human dendritic cells upon C-type lectin stimulation. Overall, our findings highlight the impact of tumor-associated glycans on dendritic cell biology and metabolism and will increase our understanding on how glycans can shape immunity.
Glioma-derived galectin-1 regulates innate and adaptive antitumor immunity
International Journal of Cancer, 2013
Galectin-1 is a glycan-binding protein, which is involved in the aggressiveness of glioblastoma (GBM) in part by stimulating angiogenesis. In different cancer models, galectin-1 has also been demonstrated to play a pivotal role in tumor-mediated immune evasion especially by modulating cells of the adaptive immune system. It is yet unknown whether the absence or presence of galectin-1 within the glioma microenvironment also causes qualitative or quantitative differences in innate and=or adaptive antitumor immune responses. All experiments were performed in the orthotopic GL261 mouse high-grade glioma model. Stable galectin-1 knockdown was achieved via transduction of parental GL261 tumor cells with a lentiviral vector encoding a galectin-1-targeting miRNA. We demonstrated that the absence of tumor-derived but not of host-derived galectin-1 significantly prolonged the survival of glioma-bearing mice as such and in combination with dendritic cell (DC)-based immunotherapy. Both flow cytometric and pathological analysis revealed that the silencing of glioma-derived galectin-1 significantly decreased the amount of brain-infiltrating macrophages and myeloid-derived suppressor cells (MDSC) in tumor-bearing mice. Additionally, we revealed a pro-angiogenic role for galectin-1 within the glioma microenvironment. The data provided in this study reveal a pivotal role for glioma-derived galectin-1 in the regulation of myeloid cell accumulation within the glioma microenvironment, the most abundant immune cell population in high-grade gliomas. Furthermore, the prolonged survival observed in untreated and DC-vaccinated glioma-bearing mice upon the silencing of tumor-derived galectin-1 strongly suggest that the in vivo targeting of tumor-derived galectin-1 might offer a promising and realistic adjuvant treatment modality in patients diagnosed with GBM. Glioblastoma (GBM) is the most frequent and malignant human brain tumor, accounting for 50% of all primary brain tumor cases in adults. 1 Despite the availability of multi-modal treatments, including maximal, safe neurosurgical resection and chemoradiotherapy, the prognosis of GBM remains dismal with a median survival expectancy of 15
Current Pharmaceutical Biotechnology, 2012
Malignant gliomas, the most common malignant primary brain tumors, have a deleterious clinical prognosis of approximately 12 months in unselected series. The resistance against antineoplastic therapy is apparently not only associated with a high proliferative potential, marked antiapoptotic resistance and high migratory capacity. Effective mechanisms to escape the immune response of the organism and an intense neoangiogenesis also contribute to the aggressive growth of these neoplasms. In addition to a number of molecular mechanisms, the group of glycohydrate-binding galectins seems to contribute to the aggressive growth of malignant gliomas. Galectin-1, -3, -4 and -8 have been shown to be overexpressed in malignant gliomas. Galectin-1 is known to be involved in glioma cell migration and possibly also in proliferation. In this review, various aspects of glioma biology and their therapeutic relevance is discussed. The role of galectins in apoptosis-resistance, immune response and angiogenesis is discussed and explained why these molecules are interesting targets of glioma therapy.
Glycan regulation in cancer, nervous and immune system: A narrative review
Biomedical Research and Therapy
Glycans are carbohydrate components of glycoconjugates, which interact with their receptors; for example, galectins and C-type lectins. The specificity to their receptors makes them the ideal biomarkers that they can be used as a therapeutic target or as a screening tool. We collected and reviewed articles from different databases, which show that glycans play a significant role in several body functions, such as stimulation of the immune system, and can be used in the differentiation among cancer types. They also help in nervous system repair, regeneration, regulation and proliferation. Furthermore, several pathogens like Schistosoma, HIV, Influenza, Candida, and Ebola produce glycoproteins to aid in the invasion via attachment to surface glycoproteins and defend themselves against the host's immune system.
Glycosylation in cancer: Selected roles in tumour progression, immune modulation and metastasis
Cellular immunology, 2018
Tumour metastasis is the main cause of cancer related deaths. Metastasis is an intricate multi-step process that requires the acquisition of several cancer cell features, including the modulation of tumour cell migration, adhesion, invasion, and immune evasion. Changes in the cellular glycosylation are associated with malignant transformation of cancer cells, tumour progression and ultimately, metastasis formation. Glycans have major impact on cellular signalling and on the regulation of tumour cell-cell adhesion and cell-matrix interaction. Glycans drive the interplay between the cancer cells and the tumour microenvironment. In this review, we summarize the roles of glycan alterations in tumour progression, such as acquisition of oncogenic features due to modulation of receptor tyrosine kinases, proteoglycans, cadherins and integrins. We also highlight the importance of key glycan binding proteins such as selectins, siglecs and galectins, which are pivotal in the modulation of immu...
Cell, 2014
The clinical benefit conferred by vascular endothelial growth factors (VEGF)-targeted therapies is variable, and tumors from treated patients eventually reinitiate growth. Here, we identify a glycosylation-dependent pathway that compensates for the absence of cognate ligand and preserves angiogenesis in response to VEGF blockade. Remodeling of the endothelial cell (EC) surface glycome selectively regulated binding of galectin-1 (Gal1), which upon recognition of complex N-glycans on VEGFR2, activated VEGF-like signaling. Vessels within anti-VEGF-sensitive tumors exhibited high levels of a2-6-linked sialic acid, which prevented Gal1 binding. In contrast, anti-VEGF refractory tumors secreted increased Gal1 and their associated vasculature displayed glycosylation patterns that facilitated Gal1-EC interactions. Interruption of b1-6GlcNAc branching in ECs or silencing of tumor-derived Gal1 converted refractory into anti-VEGF-sensitive tumors, whereas elimination of a2-6-linked sialic acid conferred resistance to anti-VEGF. Disruption of the Gal1-N-glycan axis promoted vascular remodeling, immune cell influx and tumor growth inhibition. Thus, targeting glycosylation-dependent lectin-receptor interactions may increase the efficacy of anti-VEGF treatment.
A Bitter Sweet Symphony: Immune Responses to Altered O-glycan Epitopes in Cancer
Biomolecules, 2016
The appearance of aberrant glycans on the tumor cell surface is one of the emerging hallmarks of cancer. Glycosylation is an important post-translation modification of proteins and lipids and is strongly affected by oncogenesis. Tumor-associated glycans have been extensively characterized regarding their composition and tumor-type specific expression patterns. Nevertheless whether and how tumor-associated glycans contribute to the observed immunomodulatory actions by tumors has not been extensively studied. Here, we provide a detailed overview of the current knowledge on how tumor-associated O-glycans affect the anti-tumor immune response, thereby focusing on truncated O-glycans present on epithelial tumors and mucins. These tumor-associated O-glycans and mucins bind a variety of lectin receptors on immune cells to facilitate the subsequently induction of tolerogenic immune responses. We, therefore, postulate that tumor-associated glycans not only support tumor growth, but also actively contribute to immune evasion.