Changes in glycosylation during tumour progression are a key hallmark of cancer. One of the glycan moieties generally overexpressed in cancer are sialic acids, which can induce immunomodulatory ...properties via binding to Siglec receptors. We here show that Pancreatic Ductal Adenocarcinoma (PDAC) tumour cells present an increased sialylation that can be recognized by Siglec-7 and Siglec-9 on myeloid cells. We identified the expression of the α2,3 sialyltransferases ST3GAL1 and ST3GAL4 as main contributor to the synthesis of ligands for Siglec-7 and Siglec-9 in tumour cells. Analysing the myeloid composition in PDAC, using single cell and bulk transcriptomics data, we identified monocyte-derived macrophages as contributors to the poor clinical outcome. Tumour-derived sialic acids dictate monocyte to macrophage differentiation via signalling through Siglec-7 and Siglec-9. Moreover, triggering of Siglec-9 in macrophages reduce inflammatory programmes, while increasing PD-L1 and IL-10 expression, illustrating that sialic acids modulate different myeloid cells. This work highlights a critical role for sialylated glycans in controlling immune suppression and provides new potential targets for cancer immunotherapy in PDAC.
A new polysaccharide secreted by the human opportunistic fungal pathogen Aspergillus fumigatus has been characterized. Carbohydrate analysis using specific chemical degradations, mass spectrometry, ...¹H and ¹³C nuclear magnetic resonance showed that this polysaccharide is a linear heterogeneous galactosaminogalactan composed of α1-4 linked galactose and α1-4 linked N-acetylgalactosamine residues where both monosacharides are randomly distributed and where the percentage of galactose per chain varied from 15 to 60%. This polysaccharide is antigenic and is recognized by a majority of the human population irrespectively of the occurrence of an Aspergillus infection. GalNAc oligosaccharides are an essential epitope of the galactosaminogalactan that explains the universal antibody reaction due to cross reactivity with other antigenic molecules containing GalNAc stretches such as the N-glycans of Campylobacter jejuni. The galactosaminogalactan has no protective effect during Aspergillus infections. Most importantly, the polysaccharide promotes fungal development in immunocompetent mice due to its immunosuppressive activity associated with disminished neutrophil infiltrates.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Gangliosides are sialylated glycolipids, mainly present at the cell surface membrane, involved in a variety of cellular signaling events. During malignant transformation, the composition of these ...glycosphingolipids is altered, leading to structural and functional changes, which are often negatively correlated to patient survival. Cancer cells have the ability to shed gangliosides into the tumor microenvironment, where they have a strong impact on anti-tumor immunity and promote tumor progression. Since most ganglioside species show prominent immunosuppressive activities, they might be considered checkpoint molecules released to counteract ongoing immunosurveillance. In this review, we highlight the current state-of-the-art on the ganglioside-mediated immunomodulation, specified for the different immune cells and individual gangliosides. In addition, we address the dual role that certain gangliosides play in the tumor microenvironment. Even though some ganglioside species have been more extensively studied than others, they are proven to contribute to the defense mechanisms of the tumor and should be regarded as promising therapeutic targets for inclusion in future immunotherapy regimens.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cancer stem cells (CSCs) are located in dedicated niches, where they remain inert to chemotherapeutic drugs and drive metastasis. Although plasticity in the CSC pool is well appreciated, the ...molecular mechanisms implicated in the regulation of cancer stemness are still elusive. Here, we define a fucosylation-dependent reprogramming of colon cancer cells towards a stem cell-like phenotype and function. De novo transcriptional activation of Fut9 in the murine colon adenocarcinoma cell line, MC38, followed by RNA seq-based regulon analysis, revealed major gene regulatory networks related to stemness. Lewisx, Sox2, ALDH and CD44 expression, tumorsphere formation, resistance to 5-FU treatment and in vivo tumor growth were increased in FUT9-expressing MC38 cells compared to the control cells. Likewise, human CRC cell lines highly expressing FUT9 displayed phenotypic features of CSCs, which were significantly impaired upon FUT9 knock-out. Finally, in primary CRC FUT9+ tumor cells pathways related to cancer stemness were enriched, providing a clinically meaningful annotation of the complicity of FUT9 in stemness regulation and may open new avenues for therapeutic intervention.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Aberrant glycosylation of tumor cells is recognized as a universal hallmark of cancer pathogenesis. Overexpression of fucosylated epitopes, such as type I (H1, Lewis
, Lewis
, and sialyl Lewis
) and ...type II (H2, Lewis
, Lewis
, and sialyl Lewis
) Lewis antigens, frequently occurs on the cancer cell surface and is mainly attributed to upregulated expression of pertinent fucosyltransferases (FUTs). Nevertheless, the impact of fucose-containing moieties on tumor cell biology is not fully elucidated yet. Here, we review the relevance of tumor-overexpressed FUTs and their respective synthesized Lewis determinants in critical aspects associated with cancer progression, such as increased cell survival and proliferation, tissue invasion and metastasis, epithelial corrected to mesenchymal transition, endothelial and immune cell interaction, angiogenesis, multidrug resistance, and cancer stemness. Furthermore, we discuss the potential use of enhanced levels of fucosylation as glycan biomarkers for early prognosis, diagnosis, and disease monitoring in cancer patients.
The human macrophage galactose‐type lectin (MGL), expressed on macrophages and dendritic cells (DCs), modulates distinct immune cell responses by recognizing N‐acetylgalactosamine (GalNAc) containing ...structures present on pathogens, self‐glycoproteins, and tumor cells. Herein, NMR spectroscopy and molecular dynamics (MD) simulations were used to investigate the structural preferences of MGL against different GalNAc‐containing structures derived from the blood group A antigen, the Forssman antigen, and the GM2 glycolipid. NMR spectroscopic analysis of the MGL carbohydrate recognition domain (MGL‐CRD, C181‐H316) in the absence and presence of methyl α‐GalNAc (α‐MeGalNAc), a simple monosaccharide, shows that the MGL‐CRD is highly dynamic and its structure is strongly altered upon ligand binding. This plasticity of the MGL‐CRD structure explains the ability of MGL to accommodate different GalNAc‐containing molecules. However, key differences are observed in the recognition process depending on whether the GalNAc is part of the blood group A antigen, the Forssman antigen, or GM2‐derived structures. These results are in accordance with molecular dynamics simulations that suggest the existence of a distinct MGL binding mechanism depending on the context of GalNAc moiety presentation. These results afford new perspectives for the rational design of GalNAc modifications that fine tune MGL immune responses in distinct biological contexts, especially in malignancy.
Flexibility orders binding: The carbohydrate recognition domain of human macrophage galactose‐type lectin (MGL) is highly flexible and its structure and dynamics is strongly altered upon GalNAc binding (see figure). This intrinsic plasticity dictates the ability of MGL to recognize different tumor‐associated GalNAc‐containing ligands, and key differences on MGL binding are observed depending on the GalNAc moiety presentation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Vaccination is one of the greatest achievements in biomedical research preventing death and morbidity in many infectious diseases through the induction of pathogen‐specific humoral and cellular ...immune responses. Currently, no effective vaccines are available for pathogens with a highly variable antigenic load, such as the human immunodeficiency virus or to induce cellular T‐cell immunity in the fight against cancer. The recent SARS‐CoV‐2 outbreak has reinforced the relevance of designing smart therapeutic vaccine modalities to ensure public health. Indeed, academic and private companies have ongoing joint efforts to develop novel vaccine prototypes for this virus. Many pathogens are covered by a dense glycan‐coat, which form an attractive target for vaccine development. Moreover, many tumor types are characterized by altered glycosylation profiles that are known as “tumor‐associated carbohydrate antigens”. Unfortunately, glycans do not provoke a vigorous immune response and generally serve as T‐cell‐independent antigens, not eliciting protective immunoglobulin G responses nor inducing immunological memory. A close and continuous crosstalk between glycochemists and glycoimmunologists is essential for the successful development of efficient immune modulators. It is clear that this is a key point for the discovery of novel approaches, which could significantly improve our understanding of the immune system. In this review, we discuss the latest advancements in development of vaccines against glycan epitopes to gain selective immune responses and to provide an overview on the role of different immunogenic constructs in improving glycovaccine efficacy.
In this review, the latest advancements in development of synthetic glycoconjugate vaccines in infection and cancer have been highlighted. We provide an overview on the role of different immunogenic constructs in the modulation of immune responses in cancer and in some relevant bacterial and viral infections according to the use of different carriers, the diversity of pathological epitopes targeted, and the mode of presentation to the immune system.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The C‐type lectin MGL activates the ERK‐p90RSK‐CREB axis, which together with TLR2 signaling leads to enhanced secretion of IL‐10 and TNFα.
DCs orchestrate immune responses to infectious pathogens ...and disturbances in tissue integrity. Equipped with C‐type lectins, DCs can respond to environmental changes in glycosylation. Many C‐type lectins are capable of modulating TLR activation, thereby facilitating tailor‐made immune reactions. Here, we investigated the signaling properties of the C‐type lectin MGL and show that MGL engagement by agonistic antibodies or carbohydrate ligands couples to TLR signal transduction for increased IL‐10 and TNF‐α secretion by human monocyte‐derived DCs. MGL triggering especially synergized with TLR2‐induced pathways, leading to elevated IL‐10 mRNA levels and enhanced TNF‐α mRNA stability. In addition, MGL signaling promoted phosphorylation of the MAPK ERK and the transcription factor CREB. Whereas specific inhibitors of p90RSK blocked the MGL‐induced cytokine secretion, AP‐1 was not involved. Strikingly, NF‐κB was only crucial for the IL‐10 response and dispensable for TNF‐α production. Together, our results demonstrate that MGL activation of the ERK‐p90RSK‐CREB axis converges with TLR2‐induced pathways, thereby fine‐tuning the DC maturation phenotype.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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•There is multilevel complexity in glycan-induced immune modulation.•Lectin binding is dependent on glycan constitution and carrier properties.•Multivalent presentation of glycans is ...key to novel biotechnological designs.•More insight in multivalent glycan-induced lectin signalling is necessary.
Glycans play a crucial role to discern between self and foreign entities by providing key recognition elements for C-type lectin receptors (CLRs) and Siglec receptors expressed on immune cells. The glycan recognition of CLRs has illustrated a potent immune modulatory role affecting not only innate pathogen binding and immune signalling, but also Thelper differentiation, cytokine production and antigen presentation. This broad range of influence has implicated glycans in the pathogenesis of infectious diseases but also revealed their extraordinary properties in cancer. Glycan binding by CLRs and Siglecs can be exploited for immunotherapy and the design of glycan-based therapeutics and their multivalent requirements will aspire new biotechnological approaches to effectively interfere in immunological processes in cancer and infectious diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Human cholangiocytes are continuously exposed to millimolar levels of hydrophobic bile salt monomers. We recently hypothesized that an apical biliary HCO 3− umbrella might prevent the protonation of ...biliary glycine‐conjugated bile salts and uncontrolled cell entry of the corresponding bile acids, and that defects in this biliary HCO 3− umbrella might predispose to chronic cholangiopathies. Here, we tested in vitro whether human cholangiocyte integrity in the presence of millimolar bile salt monomers is dependent on (1) pH, (2) adequate expression of the key HCO 3− exporter, anion exchanger 2 (AE2), and (3) an intact cholangiocyte glycocalyx. To address these questions, human immortalized cholangiocytes and cholangiocarcinoma cells were exposed to chenodeoxycholate and its glycine/taurine conjugates at different pH levels. Bile acid uptake was determined radiochemically. Cell viability and apoptosis were measured enzymatically. AE2 was knocked down by lentiviral short hairpin RNA. A cholangiocyte glycocalyx was identified by electron microscopy, was enzymatically desialylated, and sialylation was quantified by flow cytometry. We found that bile acid uptake and toxicity in human immortalized cholangiocytes and cholangiocarcinoma cell lines in vitro were pH and AE2 dependent, with the highest rates at low pH and when AE2 expression was defective. An apical glycocalyx was identified on cholangiocytes in vitro by electron microscopic techniques. Desialylation of this protective layer increased cholangiocellular vulnerability in a pH‐dependent manner. Conclusion: A biliary HCO 3− umbrella protects human cholangiocytes against damage by bile acid monomers. An intact glycocalyx and adequate AE2 expression are crucial in this process. Defects of the biliary HCO 3− umbrella may lead to the development of chronic cholangiopathies. (HEPATOLOGY 2012;55:173–183)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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