Siglec Family Research Articles

Targeted delivery of zoledronic acid through the sialic acid - Siglec axis for killing and reversal of M2 phenotypic tumor-associated macrophages - A promising cancer immunotherapy.

Immune checkpoint inhibitors (ICIs), like monoclonal antibodies of PD-1, CTLA-4, and their ligands, are effective only in some populations of patients with cancer, because the immunosuppressive state of the tumor microenvironment (TME) in some patients cannot be effectively reversed after ICI therapy. Sialic acid (SA) receptors in the Siglec family are highly expressed on the surface of tumor-associated macrophages (TAMs) and most have immunosuppressive effects. Therefore, targeting TAMs (the siglec axis) to reverse tumor immunosuppression may provide a new direction for the development of novel tumor immunotherapies. We designed a Zoledronic acid (ZA)-loaded liposome modified by a SA-octadecylamine conjugate (ZA-SL) to act as a novel nanomedicine delivery platform. This platform can efficiently deliver ZA to TAMs through the combination of SA and Siglec-1 and exerts specific cytotoxicity or phenotypic remodeling of M2-like TAMs depending on the drug concentration in TAMs. In vivo experiments showed that ZA-SL had good TAM targeting ability, and after treatment, the S180 tumors of mice were significantly inhibited, and the proportion of M1-like TAMs was significantly higher than that of M2-like TAMs with no significant adverse reactions in mice. Therefore, SA-modified ZA-loaded liposomes may provide a promising strategy for cancer immunotherapy.

Cullin 3 Is Crucial for Pro-B Cell Proliferation, Interacts with CD22, and Controls CD22 Internalization on B Cells.

B lymphocytes are important players of the adaptive immune system. However, not just activation of B cells but also regulation of B cell signaling is important to prevent hyperactivity and dysregulation of the immune response. Different mechanisms and proteins contribute to this balance. One of these is CD22, a member of the Siglec family. It is an inhibitory coreceptor of the BCR and inhibits B cell activation. Upon BCR stimulation, CD22-dependent inhibition of BCR signaling results in a decreased calcium mobilization. Although some CD22 binding partners have already been identified, the knowledge about the CD22 interactome is still incomplete. In this study, quantitative affinity purification-mass spectrometry enabled the delineation of the CD22 interactome in the B cell line DT40. These data will clarify molecular mechanisms and CD22 signaling events after BCR activation and revealed several new CD22-associated proteins. One new identified interaction partner is the E3 ubiquitin ligase cullin 3, which was revealed to regulate CD22 surface expression and clathrin-dependent CD22 internalization after BCR stimulation. Furthermore cullin 3 was identified to be important for B lymphocytes in general. B cell-specific cullin 3-deficient mice show reduced developing B cells in the bone marrow and a severe pro-B cell proliferation defect. Mature B cells in the periphery are also reduced and characterized by increased CD22 expression and additionally by preactivated and apoptotic phenotypes. The findings reveal novel functions of cullin 3 in B lymphocytes, namely regulating CD22 surface expression and internalization after B cell activation, as well as promoting proliferation of pro-B cells.

Trial in progress: A phase I/II, open-label, dose-escalation, safety and tolerability study of NC318 in subjects with advanced or metastatic solid tumors.

TPS3166 Background: Siglec-15 (S15) is a member of the Siglec family (Sialic acid-binding Immunoglobulin Lectins), a distinct subgroup of immunoglobulin (Ig) superfamily proteins involved in discriminating self from non-self-immune regulation (Macauley MS et al. 2014). Nonclinical models demonstrate S15 mediates suppression of T cell proliferation and negatively regulates T cell function. NC318 is a first-in-class monoclonal antibody that blocks S15-mediated immune suppression and prevents tumor growth by normalizing T cell function and restoring anti-tumor immunity in the tumor microenvironment (Wang J et al. 2019). The clinical hypothesis of this study is that NC318 targeting of S15 can improve anti-tumor immune response and provide benefit in multiple oncology indications. Methods: This is a multi-center, first in human, phase 1/2, open-label, non-randomized study to determine the safety and tolerability, define maximum tolerated dose and/or pharmacologically active dose, assess preliminary efficacy, and explore predictive and pharmacodynamic biomarkers of NC318 in subjects with advanced or metastatic solid tumors. Key eligibility criteria included measurable disease based on RECIST v1.1 and consent for collection of biopsies at screening and on treatment (optional for phase 1). Phase 1 used a 3+3 dose escalation design to determine the recommended phase 2 dose (RP2D) and schedule of NC318 while identifying drug related toxicities (DLTs). Phase 2 enrollment is limited to non-small cell lung, ovarian, head and neck, and triple negative breast cancer subjects with PD-L1 tumor proportion scores <50% (additional tumor types are being evaluated for inclusion). Ongoing exploratory analyses include the assessment of predictive biomarkers associated with treatment benefit, and pharmacodynamic markers associated with study drug activity (e.g. evaluation of tumor biopsies and peripheral markers of inflammation). Phase 1 enrollment began October 2018 and completed in August 2019. The RP2D was defined and the phase 2 opened to enrollment October 2019. Clinical trial information: NCT03665285 .

Abstract A95: A genome-wide CRISPR screen identifies novel ligands for the Siglec family of glyco-immune checkpoint receptors

Abstract Cancer cells are frequently characterized by extensive remodeling of their cell surface glycocalyx, the complex pattern of sugar modifications that decorate cell surface proteins. In particular, cancer cells often overexpress an unusually high density of sialic acid glycans on their plasma membrane. This modification shields tumors from immune detection through engagement of inhibitory Siglec (Sialic acid-binding immunoglobulin-type lectin) receptors, which are widely expressed in innate immune cells. Blockade of these Siglec-based immune checkpoints has shown the potential to increase immune activity against highly sialylated cancer cells. The specific glycosylated ligands that serve as counter-receptors for Siglecs, however, are not well characterized. Here we describe a strategy for better defining these immune checkpoints using a CRISPR-based genetic screening approach. A library of gRNAs was screened using FACS to identify genes whose ablation significantly reduced cell-surface binding of recombinantly expressed, fluorescently labeled Siglecs. We thereby generated a list of genes with putative roles in driving the cell-surface expression of sialic acid-containing Siglec ligands. Our screen correctly identified known genes involved in sialic acid biosynthesis, validating the specificity of this approach. Additionally, this screen revealed that knockdown of a single heavily O-glycosylated protein plasma membrane protein dramatically reduced binding of Siglec7, the Siglec receptor expressed specifically in NK cells. Follow-up work has shown that Siglec7 binds to this ligand with high affinity and that genetic blockade of this interaction potentiates NK cell killing activity in vitro. This study has thus defined a novel and specific glyco-immune interaction with potential significance in driving tumor escape from innate immune surveillance. Citation Format: Simon Wisnovsky, Carolyn Bertozzi. A genome-wide CRISPR screen identifies novel ligands for the Siglec family of glyco-immune checkpoint receptors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A95.

NK Cell-Based Immune Checkpoint Inhibition.

Immunotherapy, with an increasing number of therapeutic dimensions, is becoming an important mode of treatment for cancer patients. The inhibition of immune checkpoints, which are the source of immune escape for various cancers, is one such immunotherapeutic dimension. It has mainly been aimed at T cells in the past, but NK cells are a newly emerging target. Simultaneously, the number of checkpoints identified has been increasing in recent times. In addition to the classical NK cell receptors KIRs, LIRs, and NKG2A, several other immune checkpoints have also been shown to cause dysfunction of NK cells in various cancers and chronic infections. These checkpoints include the revolutionized CTLA-4, PD-1, and recently identified B7-H3, as well as LAG-3, TIGIT & CD96, TIM-3, and the most recently acknowledged checkpoint-members of the Siglecs family (Siglec-7/9), CD200 and CD47. An interesting dimension of immune checkpoints is their candidacy for dual-checkpoint inhibition, resulting in therapeutic synergism. Furthermore, the combination of immune checkpoint inhibition with other NK cell cytotoxicity restoration strategies could also strengthen its efficacy as an antitumor therapy. Here, we have undertaken a comprehensive review of the literature to date regarding NK cell-based immune checkpoints.

Siglecs as Immune Cell Checkpoints in Disease.

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are expressed on the majority of white blood cells of the immune system and play critical roles in immune cell signaling. Through recognition of sialic acid-containing glycans as ligands, they help the immune system distinguish between self and nonself. Because of their restricted cell type expression and roles as checkpoints in immune cell responses in human diseases such as cancer, asthma, allergy, neurodegeneration, and autoimmune diseases they have gained attention as targets for therapeutic interventions. In this review we describe the Siglec family, its roles in regulation of immune cell signaling, current efforts to define its roles in disease processes, and approaches to target Siglecs for treatment of human disease.

Integrative Analysis of Siglec-15 mRNA in Human Cancers Based on Data Mining.

Objective: Cancer is expected to be the leading cause of death worldwide within the 21st century and is the single most important obstacle to extending life expectancy. Unfortunately, the most effective approach to combating cancers remains a complex and unsolved problem. Siglec-15 is a member of the Siglec family and plays a conserved regulatory role in the immune system of vertebrates. Previous studies on Siglec-15 have focused on its function in osteoclast regulation. The purpose of this study was to explore the significance of Siglec-15 mRNA in human cancer mainly based on information obtained from online databases.Method: Data were collected from several online databases. Serial analysis of gene expression (SAGE) and Virtual Northern, UALCAN Database Analysis, Catalog of Somatic Mutations in Cancer (COSMIC) analysis, the cBio cancer genomics portal, Cancer Regulome tools and data, Kaplan-Meier Plotter Analysis and the UCSC Xena website were used to analyze the data.Results: Compared with normal tissues, Siglec-15 up-regulation was widely observed in tuomrs. Differences in Siglec-15 expression were associated with different prognoses. Siglec-15 mutations are widely observed in tumors and interact with different genes in different cancer types.Conclusion: Siglec-15 is a potential target for the expansion of cancer immunotherapy.

Siglecs, Novel Immunotherapy Targets, Potentially Enhance The Effectiveness of Existing Immune Checkpoint Inhibitors in Glioma Immunotherapy.

BackgroundInhibitors of immune checkpoints have shown little effect in clinical trials involving glioma patients. Here, we explored novel targets for use in future treatments. Previous studies showed the sialic acid-binding Ig-like lectin (Siglec) family to have a specific role in immunosuppression. We aimed to study the characteristics and immune function of Siglec family members.MethodsTranscriptome data from 1024 glioma samples and 1551 glioma single cells were used in our study. Clinical and molecular pathology information was also included. Statistical, bioinformatical methods, and single-cell sequencing analysis were applied to investigate the role of Siglec family members.ResultsSiglecs-5, −7, −9, and −16 showed a significant correlation with immunosuppression in glioma. They are typically expressed in higher grade, IDH-wildtype, and mesenchymal subtype gliomas. Siglec-5, −7, and −9 had a similar immune function to TIM-3, while Siglec-16 was similar to PD-L1, suppressing tumor immunity via different mechanisms. Joint use of Siglec-inhibitors and immune checkpoint inhibitors could prolong the survival of glioma patients.ConclusionSiglec-5, −7, −9, and −16 suppressed tumor immunity in different ways. Joint usage of inhibitors may be an effective means to improve the efficacy of glioma immunotherapy.

A Sulfonamide Sialoside Analogue for Targeting Siglec-8 and -F on Immune Cells.

The Siglec family of cell surface receptors have emerged as attractive targets for cell-directed therapies due to their restricted expression on immune cells, endocytic properties, and ability to modulate receptor signaling. Human Siglec-8, for instance, has been identified as a therapeutic target for the treatment of eosinophil and mast cell disorders. A promising strategy to target Siglecs involves the use of liposomal nanoparticles with a multivalent display of Siglec ligands. A key challenge for this approach is the identification of a high affinity ligand for the target Siglec. Here, we report the development of a ligand of Siglec-8 and its closest murine functional orthologue Siglec-F that is capable of targeting liposomes to cells expressing Siglec-8 or -F. A glycan microarray library of synthetic 9-N-sulfonyl sialoside analogues was screened to identify potential lead compounds. The best ligand, 9-N-(2-naphthyl-sulfonyl)-Neu5Acα2-3-[6-O-sulfo]-Galβ1-4GlcNAc (6'-O-sulfo NSANeu5Ac) combined the lead 2-naphthyl sulfonyl C-9 substituent with the preferred sulfated scaffold. The ligand 6'-O-sulfo NSANeu5Ac was conjugated to lipids for display on liposomes to evaluate targeted delivery to cells. Targeted liposomes showed strong in vitro binding/uptake and selectivity to cells expressing Siglec-8 or -F and, when administered to mice, exhibit in vivo targeting to Siglec-F+ eosinophils.

Expression profiling of immune inhibitory Siglecs and their ligands in patients with glioma

Gliomas appear to be highly immunosuppressive tumors, with a strong myeloid component. This includes MDSCs, which are a heterogeneous, immature myeloid cell population expressing myeloid markers Siglec-3 (CD33) and CD11b and lacking markers of mature myeloid cells including MHC II. Siglec-3 is a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family and has been suggested to promote MDSC expansion and suppression. Siglecs form a recently defined family of receptors with potential immunoregulatory functions but only limited insight in their expression on immune regulatory cell subsets, prompting us to investigate Siglec expression on MDSCs. We determined the expression of different Siglec family members on monocytic-MDSCs (M-MDSCs) and polymorphnuclear-MDSCs (PMN-MDSCs) from blood of glioma patients and healthy donors, as well as from patient-derived tumor material. Furthermore, we investigated the presence of sialic acid ligands for these Siglecs on MDSCs and in the glioma tumor microenvironment. Both MDSC subsets express Siglec-3, -5, -7 and -9, with higher levels of Siglec-3, -7 and -9 on M-MDSCs and higher Siglec-5 levels on PMN-MDSCs. Similar Siglec expression profiles were found on MDSCs from healthy donors. Furthermore, the presence of Siglec-5 and -9 was also confirmed on PMN-MDSCs from glioma tissue. Interestingly, freshly isolated glioma cells predominantly expressed sialic acid ligands for Siglec-7 and -9, which was confirmed in situ. In conclusion, our data show a distinct Siglec expression profile for M- and PMN-MDSCs and propose possible sialic acid–Siglec interactions between glioma cells and MDSCs in the tumor microenvironment.

Detection of CD33 expression on monocyte surface is influenced by phagocytosis and temperature.

CD33 is a myeloid-associated marker and belongs to the sialic acid-binding immunoglobulin (Ig)-like lectin (Siglec) family. Such types of receptors are highly expressed in acute myeloid leukemia, which could be used in its treatment. CD33 shows high variability in its expression levels with still unknown reasons. Here, we investigated the CD33 expression of monocytes in human blood samples processed at different temperatures and in dependence on their phagocytic activity against opsonized Escherichia coli. The samples were stained by fluorescently labelled anti-human CD14 to specify the monocyte population, anti-human CD33 antibodies to evaluate CD33 expression and analyzed by flow cytometry and confocal laser scanning microscopy. In blood samples kept at 37°C or first pre-chilled at 0°C with subsequent warming up to 37°C, the percentage of CD33-positive monocytes as well as their relative fluorescence intensity was up-regulated compared to samples kept constantly at 0°C. After exposure to E. coli the CD33 relative fluorescence intensity of the monocytes activated at 37°C was 3 to 4 times higher than that of those cells kept inactive at 0°C. Microscopic analysis showed internalisation of CD33 due to its enhanced expression on the surface followed by engulfment of E. coli.

B Cell Siglecs-News on Signaling and Its Interplay With Ligand Binding.

CD22 and Siglec-G are members of the Siglec family. Both are inhibitory co-receptors on the surface of B cells and inhibit B-cell receptor induced signaling, characterized by inhibition of the calcium mobilization and cellular activation. CD22 functions predominantly as an inhibitor on conventional B cells, while Siglec-G is an important inhibitor on the B1a-cell subset. These two B-cell Siglecs do not only inhibit initial signaling, but also have an important function in preventing autoimmunity, as double deficient mice develop a lupus-like phenotype with age. Siglecs are characterized by their conserved ability to bind terminal sialic acid of glycans on the cell surface, which is important to regulate the inhibitory role of Siglecs. While CD22 binds α2,6-linked sialic acids, Siglec-G can bind both α2,6-linked and α2,3-linked sialic acids. Interestingly, ligand binding is differentially regulating the ability of CD22 and Siglec-G to control B-cell activation. Within the last years, quite a few studies focused on the different functions of B-cell Siglecs and the interplay of ligand binding and signal inhibition. This review summarizes the role of CD22 and Siglec-G in regulating B-cell receptor signaling, membrane distribution with the importance of ligand binding, preventing autoimmunity and the role of CD22 beyond the naïve B-cell stage. Additionally, this review article features the long time discussed interaction between CD45 and CD22 with highlighting recent data, as well as the interplay between CD22 and Galectin-9 and its influence on B-cell receptor signaling. Moreover, therapeutical approaches targeting human CD22 will be elucidated.

Evolution of sialic acids: Implications in xenotransplant biology.

All living cells are covered with a dense “sugar-coat” of carbohydrate chains (glycans) conjugated to proteins and lipids. The cell surface glycome is determined by a non-template driven process related to the collection of enzymes that assemble glycans in a sequential manner. In mammals, many of these glycans are topped with sialic acids (Sia), a large family of acidic sugars. The “Sialome” is highly diverse owing to various Sia types, linkage to underlying glycans, range of carriers, and complex spatial organization. Presented at the front of cells, Sia play a major role in immunity and recognition of “self” versus “non-self,” largely mediated by the siglecs family of Sia-binding host receptors. Albeit many mammalian pathogens have evolved to hijack this recognition system to avoid host immune attack, presenting a fascinating host-pathogen evolutionary arms race. Similarly, cancer cells exploit Sia for their own survival and propagation. As part of this ongoing fitness, humans lost the ability to synthesize the Sia type N-glycolylneuraminic acid (Neu5Gc), in contrast to other mammals. While this loss had provided an advantage against certain pathogens, humans are continuously exposed to Neu5Gc through mammalian-derived diet (eg, red meat), consequently generating a complex immune response against it. Circulating anti-Neu5Gc antibodies together with Neu5Gc on some human tissues mediate chronic inflammation “xenosialitis” that exacerbate various human diseases (eg, cancer and atherosclerosis). Similarly, Neu5Gc-containing xenografts are exposed to human anti-Neu5Gc antibodies with implications to sustainability. This review aimed to provide a glimpse into the evolution of Sia and their implications to xenotransplantation.

Structural studies on ligand binding ability of Siglec-2 using molecular modeling techniques

Siglecs are attractive therapeutic target of the major homologous subfamily of I-type lectins. The primary role of Siglecs may actually lie in the recognition and phagocytosis of bacterial pathogens that express sialic acids, maintenance of myelin organization, and inhibition of neurite outgrowth, cell-cell interactions between neurons and glial cells etc. Siglec-2, a member of the Siglec family expressed on the surface of maturing B cells and B cell lymphomas and regulates signal transduction. In this work, 3-D structure of human Siglec-2 was predicted using molecular modeling techniques. The structure of the complex in solution of Siglec-2 with ligand, 6′-Sialyl-N-acetyl lactose (6′-SialylLacNAc) was predicted using a novel docking technique. The structural analysis of the complex and calculation of theoretical dissociation constant value will help to ascertain functional roles of such sugar binding protein.

Murine Red Blood Cells Lack Ligands for B Cell Siglecs, Allowing Strong Activation by Erythrocyte Surface Antigens.

CD22 and sialic acid-binding Ig-like lectin (Siglec)-G are members of the Siglec family of inhibitory coreceptors expressed on B cells that participate in enforcement of peripheral B cell tolerance. We have shown previously that when a BCR engages its cognate Ag on a cell surface that also expresses Siglec ligands, B cell Siglecs are recruited to the immunological synapse, resulting in suppression of BCR signaling and B cell apoptosis. Because all cells display sialic acids, and CD22 and Siglec-G have distinct, yet overlapping, specificities for sialic acid-containing glycan ligands, any cell could, in principle, invoke this tolerogenic mechanism for cell surface Ags. However, we show in this article that C57BL/6J mouse RBCs are essentially devoid of CD22 and Siglec-G ligands. As a consequence, RBCs that display a cell surface Ag, membrane-bound hen egg lysozyme, strongly activate Ag-specific B cells. We reasoned that de novo introduction of CD22 ligands in RBCs should abolish B cell activation toward its cognate Ag on the surface of RBCs. Accordingly, we used a glyco-engineering approach wherein synthetic CD22 ligands linked to lipids are inserted into the membrane of RBCs. Indeed, insertion of CD22 ligands into the RBC cell surface strongly inhibited B cell activation, cytokine secretion, and proliferation. These results demonstrate that the lack of Siglec ligands on the surface of murine RBCs permits B cell responses to erythrocyte Ags and show that Siglec-mediated B cell tolerance is restricted to cell types that express glycan ligands for the B cell Siglecs.

Sialic Acids in the Immune Response during Sepsis.

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are a group of cell surface transmembrane receptors expressed on immune cells, and regulate immune balance in inflammatory diseases. Sepsis is a life-threatened inflammatory syndrome induced by infection, and the pathogenesis of sepsis includes immune dysregulation, inflammation, and coagulation disorder. Here, we reviewed the various roles acted by Siglecs family in the pathogenesis of sepsis. Siglec-1, Siglec-5, and Siglec-14 play bidirectional roles through modulation of inflammation and immunity. Siglec-2 regulates the immune balance during infection by modulating B cell and T cell response. Siglec-9 helps endocytosis of toll-like receptor 4, regulates macrophages polarization, and inhibits the function of neutrophils during infection. Siglec-10 inhibits danger-associated molecular patterns induced inflammation, helps the initiation of antigen response by T cells, and decreases B-1a cell population to weaken inflammation. Regulating the Siglecs function in the different stages of sepsis holds great potential in the therapy of sepsis.

Human CD22 Inhibits Murine B Cell Receptor Activation in a Human CD22 Transgenic Mouse Model.

CD22, a sialic acid-binding Ig-type lectin (Siglec) family member, is an inhibitory coreceptor of the BCR with established roles in health and disease. The restricted expression pattern of CD22 on B cells and most B cell lymphomas has made CD22 a therapeutic target for B cell-mediated diseases. Models to better understand how in vivo targeting of CD22 translates to human disease are needed. In this article, we report the development of a transgenic mouse expressing human CD22 (hCD22) in B cells and assess its ability to functionally substitute for murine CD22 (mCD22) for regulation of BCR signaling, Ab responses, homing, and tolerance. Expression of hCD22 on transgenic murine B cells is comparable to expression on human primary B cells, and it colocalizes with mCD22 on the cell surface. Murine B cells expressing only hCD22 have identical calcium (Ca2+) flux responses to anti-IgM as mCD22-expressing wild-type B cells. Furthermore, hCD22 transgenic mice on an mCD22-/- background have restored levels of marginal zone B cells and Ab responses compared with deficiencies observed in CD22-/- mice. Consistent with these observations, hCD22 transgenic mice develop normal humoral responses in a peanut allergy oral sensitization model. Homing of B cells to Peyer's patches was partially rescued by expression of hCD22 compared with CD22-/- B cells, although not to wild-type levels. Notably, Siglec-engaging antigenic liposomes formulated with an hCD22 ligand were shown to prevent B cell activation, increase cell death, and induce tolerance in vivo. This hCD22 transgenic mouse will be a valuable model for investigating the function of hCD22 and preclinical studies targeting hCD22.

Glycobiology of Eosinophilic Inflammation: Contributions of Siglecs, Glycans, and Other Glycan-Binding Proteins.

The historical focus on protein–protein interactions in biological systems, at the expense of attention given to interactions between other classes of molecules, has overlooked important and clinically relevant processes and points of potential clinical intervention. For example, the significance of protein–carbohydrate interactions, especially in the regulation of immune responses, has recently received greater recognition and appreciation. This review discusses several ways by which cell-surface lectin–glycan interactions can modulate eosinophil function, particularly at the levels of eosinophil recruitment and survival, and how such interactions can be exploited therapeutically. A primary focus is on discoveries concerning Siglec-8, a glycan-binding protein selectively expressed on human eosinophils, and its closest functional paralog in the mouse, Siglec-F. Recent advances in the synthesis of polymeric ligands, the identification of physiological ligands for Siglec-8 and Siglec-F in the airway, and the determination of the basis of glycan ligand discrimination of Siglec-8 are discussed. Important similarities and differences between these siglecs are outlined. Eosinophil expression of additional glycan-binding proteins or their glycan ligands, including interactions involving members of the selectin, galectin, and siglec families, is summarized. The roles of these molecules in eosinophil recruitment, survival, and inflammation are described. Finally, the modulation of these interactions and potential therapeutic exploitation of glycan-binding proteins and their ligands to ameliorate eosinophil-associated diseases are considered.

Enhancement of Siglec-8 expression predicts adverse prognosis in patients with clear cell renal cell carcinoma

PurposeSialic acid-binding immunoglobulin-like lectins (siglecs) family has important functions in tumor progression. The purpose of our study is to figure out the correlation between the expression level of Siglec-8 and prognosis of patients with clear cell renal cell carcinoma (ccRCC), and then to predict the overall survival (OS) via a novel nomogram. Materials and methodsA group of patients (n = 267) histologically diagnosed with ccRCC from Zhongshan Hospital were included into our study. Immunohistochemistry of Siglec-8 was performed in the tissue microarray, and the staining intensity was divided into high/low according to the median value of the H-score grading. Survival analyses including Kaplan-Meier analyses and Cox regression analyses were performed to evaluate the association between Siglec-8 expression and the survival of patients in different risk groups. Stage, size, grade, and necrosis score and University of California Los Angeles Integrated Staging System score were used in the risk stratification. A nomogram incorporating Siglec-8 and several other clinical parameters was plotted for predicting the 5-year and 8-year OS. ResultsSiglec-8 was observed dominantly on the membrane of tumor cells. The enhanced expression level of Siglec-8 had significant correlation with adverse overall and disease-free survival of patients (P<0.0001 and P = 0.0186, respectively). The association was more significant in patients with lower risk. Cox regression analyses defined Siglec-8 as an independent prognostic factor of OS (P<0.001 for univariate analysis, P = 0.003 for multivariate analysis). The new nomogram integrating Siglec-8 with several traditional prognostic factors proved to be more accurate than conventional prognostic system using tumor node metastasis stage only (Harrell c-index: 0.801, 95% CI: 0.755–0.847 vs. 0.717, 95% CI: 0.662–0.772). ConclusionOur study has found that the elevated expression level of Siglec-8 was correlated with poor prognosis of patients with ccRCC. Siglec-8, incorporation with other clinical parameters, could perform better in prediction of patients׳ OS.

New Human CD22/Siglec-2 Ligands with a Triazole Glycoside.

CD22 is a member of the Siglec family. Considerable attention has been drawn to the design and synthesis of new Siglec ligands to explore target biology and innovative therapies. In particular, CD22-ligand-targeted nanoparticles with therapeutic functions have proved successful in preclinical settings for blood cancers, autoimmune diseases, and tolerance induction. Here we report the design, synthesis and affinity evaluation of a new class of Siglec ligands: namely sialic acid derivatives with a triazole moiety replacing the natural glycoside oxygen atom. In addition, we describe important and surprising differences in binding to CD22 expressed at the cell surface for compounds with distinct valences. The new class of compounds might serve as a template for the design of ligands for other members of the Siglec family and next-generation CD22-ligand-based targeted therapies.