Sialic Acid Mimetics to Target the Sialic Acid–Siglec Axis Büll, Christian; Heise, Torben; Adema, Gosse J. ...
Trends in biochemical sciences (Amsterdam. Regular ed.),
June 2016, 2016-06-00, 20160601, Letnik:
41, Številka:
6
Journal Article
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Sialic acid sugars are vital regulators of the immune system through binding to immunosuppressive sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on immune cells. Aberrant sialic ...acid–Siglec interactions are associated with an increasing number of pathologies including infection, autoimmunity, and cancer. Therefore, the sialic acid–Siglec axis is an emerging target to prevent or affect the course of several diseases. Chemical modifications of the natural sialic acid ligands have led to sialic acid mimetics (SAMs) with improved binding affinity and selectivity towards Siglecs. Recent progress in glycobiotechnology allows the presentation of these SAMs on nanoparticles, polymers, and living cells via bioorthogonal synthesis. These developments now enable the detailed study of the sialic acid–Siglec axis including its therapeutic potential as an immune modulator.
Sialic acid sugars are emerging as important regulators of the immune system through binding to immunosuppressive sialic acid-binding immunoglobulin-like lectin (Siglec) receptors.
Aberrant sialic acid–Siglec interactions are associated with multiple diseases like autoimmunity, infection, and cancer.
Recent advances now enable the synthesis of chemically modified sialic acid mimetics with high Siglec binding affinity that can be coupled to nanoparticles, polymers, or surface glycoproteins and glycolipids of living cells.
The potent immune modulatory properties of sialic acid mimetics provide a strong rationale for therapeutic targeting of the sialic acid–Siglec axis.
Sialic acids sweeten a tumor's life Büll, Christian; Stoel, Marieke A; den Brok, Martijn H ...
Cancer research (Chicago, Ill.),
06/2014, Letnik:
74, Številka:
12
Journal Article
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Over four decades ago, specific tumor characteristics were ascribed to the increased expression of sialic acid sugars on the surface of cancer cells, and this led to the definition of sialic acids as ...potential therapeutic targets. Recent advances in glycobiology and cancer research have defined the key processes underlying aberrant expression of sialic acids in cancer, and its consequences, more precisely. These consequences include effects on tumor growth, escape from apoptosis, metastasis formation, and resistance to therapy. Collectively, these novel insights provide further rationale for the design and development of therapeutic approaches that interfere with excessively high expression of sialic acids in cancer cells. Strategies to target aberrant sialylation in cancer, however, have evolved comparatively slowly. Here, we review recent findings that emphasize the detrimental effects of hypersialylation on multiple aspects of tumor growth and behavior. We also discuss novel therapeutic strategies.
Summary
Myeloid‐derived suppressor cells (MDSC) and regulatory T (Treg) cells are major components of the immune suppressive tumour microenvironment (TME). Both cell types expand systematically in ...preclinical tumour models and promote T‐cell dysfunction that in turn favours tumour progression. Clinical reports show a positive correlation between elevated levels of both suppressors and tumour burden. Recent studies further revealed that MDSCs can modulate the de novo development and induction of Treg cells. The overlapping target cell population of Treg cells and MDSCs is indicative for the importance and flexibility of immune suppression under pathological conditions. It also suggests the existence of common pathways that can be used for clinical interventions aiming to manipulate the TME. Elimination or reprogramming of the immune suppressive TME is one of the major current challenges in immunotherapy of cancer. Interestingly, recent findings suggest that natural killer T (NKT) cells can acquire the ability to convert immunosuppressive MDSCs into immunity‐promoting antigen‐presenting cells. Here we will review the cross‐talk between MDSCs and other immune cells, focusing on Treg cells and NKT cells. We will consider its impact on basic and applied cancer research and discuss how targeting MDSCs may pave the way for future immunocombination therapies.
Sialic acid sugar-carrying glycans, sialoglycans, are aberrantly expressed on many tumor cells and have emerged as potent regulatory molecules involved in creating a tumor-supportive ...microenvironment. Sialoglycans can be recognized by sialic acid-binding immunoglobulin-like lectins (Siglecs), a family of immunomodulatory receptors. Most mammalian Siglecs transmit inhibitory signals comparable with the immune checkpoint inhibitor programmed death protein 1 (PD-1), but some are activating. Recent studies have shown that tumor cells can exploit sialoglycan–Siglec interactions to modulate immune cell function, contributing to an immunosuppressive tumor microenvironment (TME). Interference with sialoglycan synthesis or sialoglycan–Siglec interactions might improve antitumor immunity. Many questions regarding specificity, signaling, and regulatory function of sialoglycan–Siglec interactions remain. We posit that sialoglycans and Siglecs present as potential glyco-immune ‘checkpoints’ for cancer immunotherapy.
Aberrant sialic acid sugar expression is commonly found in different cancer types and immune cells express immunomodulatory Siglec receptors that can recognize these sialic acids in humans and mice. Recently, high expression of Siglecs was found on several immune cells within the tumor microenvironment (TME).Recent studies, using human samples and mouse models, indicate that sialoglycan–Siglec interactions in the TME can suppress effector immune cell activity and modulate myeloid cell functions, thus contributing to tumor immune evasion and sustained tumor growth.The individual contribution of the 14 Siglec family members to immune evasion and their precise sialoglycan ligands in the TME remain to be elucidated.Sialoglycans and Siglecs might represent immune ‘checkpoints’ that should be further explored as potential targets for cancer immunotherapy.
The structural diversity of glycans on cells—the glycome—is vast and complex to decipher. Glycan arrays display oligosaccharides and are used to report glycan hapten binding epitopes. Glycan arrays ...are limited resources and present saccharides without the context of other glycans and glycoconjugates. We used maps of glycosylation pathways to generate a library of isogenic HEK293 cells with combinatorially engineered glycosylation capacities designed to display and dissect the genetic, biosynthetic, and structural basis for glycan binding in a natural context. The cell-based glycan array is self-renewable and reports glycosyltransferase genes required (or blocking) for interactions through logical sequential biosynthetic steps, which is predictive of structural glycan features involved and provides instructions for synthesis, recombinant production, and genetic dissection strategies. Broad utility of the cell-based glycan array is demonstrated, and we uncover higher order binding of microbial adhesins to clustered patches of O-glycans organized by their presentation on proteins.
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•Human glycosyltransferases (170 GTf genes) organized in glycosylation pathway maps•The human glycome displayed in a natural context on the cell surface•Sustainable cell-based array resource to dissect biological functions of glycans•Microbial adhesins may bind to clustered patches of O-glycans
Narimatsu et al. display the diversity of human sugars on the surface of a library of cells by genetically engineering the cellular glycosylation machinery. Sugars on the cell surface play important roles in interactions with the environment, and the cell library developed opens for studies of biological interactions with sugars.
Over the last decades, vaccine development has advanced significantly in pursuing higher safety with less side effects. However, this is often accompanied by a reduction in vaccine immunogenicity and ...an increased dependency on adjuvants to enhance vaccine potency. Especially for diseases like cancer, it is important that therapeutic vaccines contain adjuvants that promote strong T cell responses. An important mode of action for such adjuvants is to prolong antigen exposure to dendritic cells (DCs) and to induce their maturation. These mature DCs are extremely effective in the activation of antigen-specific T cells, which is a pre-requisite for induction of potent and long-lasting cellular immunity. For the activation of CD8
cytotoxic T cell responses, however, the exogenous vaccine antigens need to gain access to the endogenous MHCI presentation pathway of DCs, a process referred to as antigen cross-presentation. In this review, we will focus on recent insights in clinically relevant vaccine adjuvants that impact DC cross-presentation efficiency, including aluminum-based nanoparticles, saponin-based adjuvants, and Toll-like receptor ligands. Furthermore, we will discuss the importance of adjuvant combinations and highlight new developments in cancer vaccines. Understanding the mode of action of adjuvants in general and on antigen cross-presentation in DCs in particular will be important for the design of novel adjuvants as part of vaccines able to induce strong cellular immunity.
Tumor ablation technologies, such as radiofrequency-, cryo- or high-intensity focused ultrasound (HIFU) ablation will destroy tumor tissue in a minimally invasive manner. Ablation generates large ...volumes of tumor debris in situ, releasing multiple bio-molecules like tumor antigens and damage-associated molecular patterns. To initiate an adaptive antitumor immune response, antigen-presenting cells need to take up tumor antigens and, following activation, present them to immune effector cells. The impact of the type of tumor ablation on the precise nature, availability and suitability of the tumor debris for immune response induction, however, is poorly understood. In this review, we focus on immune effects after HIFU-mediated ablation and compare these to findings using other ablation technologies. HIFU can be used both for thermal and mechanical destruction of tissue, inducing coagulative necrosis or subcellular fragmentation, respectively. Preclinical and clinical results of HIFU tumor ablation show increased infiltration and activation of CD4
+
and CD8
+
T cells. As previously observed for other types of tumor ablation technologies, however, this ablation-induced enhanced infiltration alone appears insufficient to generate consistent protective antitumor immunity. Therapies combining ablation with immune stimulation are therefore expected to be key to boost HIFU-induced immune effects and to achieve systemic, long-lasting, antitumor immunity.
Lipid droplets (LDs) were initially described as fat storage organelles in adipocytes, but are increasingly recognized as dynamic players in lipid metabolism, with important roles not only in ...diseases such as diabetes and cancer, but also in immune regulation. Alterations in immune cell function, such as myeloid cell activation, are connected to profound changes in LD numbers and LD protein composition. Thus, these organelles appear to be essential to metabolically support immune responses, and have a vital role in antigen crosspresentation, interferon (IFN) responses, production of inflammatory mediators, and pathogen clearance. Here, we review recent studies that report on the role of LDs in the modulation of immune cell function, primarily focusing on myeloid cells, such as macrophages and dendritic cells (DCs).
LDs are intracellular energy storage organelles, but studies in macrophages and, more recently, DCs have highlighted their role in immune regulation. For example, LDs have a critical role in IFN responses and antigen crosspresentation.
Different LDs, with unique protein or lipid compositions, appear to exist in specific cells or even within one cell. Different types of immune activation are also reflected by modification of the LD profiles, tied to changes in cellular metabolism.
Although the presence of LDs mostly appears to be correlated with positive immunological outcome, the LDs found in cancer or upon exposure to oxidized lipids are associated with unproductive immune responses.
•Radiotherapy affects immune populations in the TME, including MDSCs.•Conventional fractionated radiation schedules are associated with MDSC recruitment.•Radiotherapy, inflammation and hypoxia play a ...role in MDSC function and recruitment.•Both MDSC-intrinsic and -extrinsic STING signaling are able to alter MDSC behavior.•Future studies should focus on elucidating a potential role of cGAS in MDSC function.
Myeloid derived suppressor cells (MDSCs) are a highly heterogeneous population of immature immune cells with immunosuppressive functions that are recruited to the tumor microenvironment (TME). MDSCs promote tumor growth and progression by inhibiting immune effector cell proliferation and function. MDSCs are affected by both novel anti-cancer therapies targeting the immune system to promote anti-tumor immunity, as well as by conventional treatments such as radiotherapy. Following radiotherapy, cytoplasmic double stranded DNA stimulates the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, resulting in type I interferon production. Effectiveness of radiotherapy and cGAS/STING signaling are closely intertwined: activation of cGAS and STING is key to generate systemic anti-tumor immunity after irradiation. This review focuses on how radiotherapy and cGAS/STING signaling in MDSCs and/or tumor cells impact MDSC recruitment, expansion and function. The influence of conventional and ablative radiotherapy treatment schedules, inflammatory response following radiotherapy, and hypoxia are discussed as MDSC modulators.
Siglecs are a family of sialic acid-binding receptors expressed by cells of the immune system and a few other cell types capable of modulating immune cell functions upon recognition of sialoglycan ...ligands. While human Siglecs primarily bind to sialic acid residues on diverse types of glycoproteins and glycolipids that constitute the sialome, their fine binding specificities for elaborated complex glycan structures and the contribution of the glycoconjugate and protein context for recognition of sialoglycans at the cell surface are not fully elucidated. Here, we generated a library of isogenic human HEK293 cells with combinatorial loss/gain of individual sialyltransferase genes and the introduction of sulfotransferases for display of the human sialome and to dissect Siglec interactions in the natural context of glycoconjugates at the cell surface. We found that Siglec-4/7/15 all have distinct binding preferences for sialylated GalNAc-type O-glycans but exhibit selectivity for patterns of O-glycans as presented on distinct protein sequences. We discovered that the sulfotransferase CHST1 drives sialoglycan binding of Siglec-3/8/7/15 and that sulfation can impact the preferences for binding to O-glycan patterns. In particular, the branched Neu5Acα2-3(6-
-sulfo)Galβ1-4GlcNAc (6'-Su-SLacNAc) epitope was discovered as the binding epitope for Siglec-3 (CD33) implicated in late-onset Alzheimer's disease. The cell-based display of the human sialome provides a versatile discovery platform that enables dissection of the genetic and biosynthetic basis for the Siglec glycan interactome and other sialic acid-binding proteins.
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