Статті в журналах: "Siglec- 9"

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Molina, Irina Miralda, Nyssa Becker Samanas та Adrian Martin Piliponsky. "Ligation of Siglec-9 inhibits FcɛRI-dependent mediator release from human mast cells". Journal of Immunology 208, № 1_Supplement (1 травня 2022): 49.18. http://dx.doi.org/10.4049/jimmunol.208.supp.49.18.

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Abstract Mast cell activation is critical for the development of allergic diseases. Ligation of Sialic acid-binding immunoglobin-like lectins (Siglecs) such as Siglec-7 and 8 has been shown to inhibit mast cell activation and is considered one of the main approaches to reduce mast cell contribution to allergic disease. Recent high throughput studies provided evidence that human mast cells express Siglec-9, an inhibitory receptor that is mainly expressed by innate immune cells such as neutrophils, monocytes and eosinophils. Based on this evidence, we aimed to examine Siglec-9 expression and function in human mast cells. Flow cytometry analysis showed that Siglec-9 is expressed in the human mast cell lines LAD2, LUVA, and HMC-1, and in peripheral blood-derived cultured human mast cells (PBCMCs). The expression of Siglec-9 in PBCMCs peaks at week 5 of culture and correlates positively with the expression of the high affinity receptor for IgE (FcɛRI). Pre-treatment of human mast cells with the Siglec-9 agonists glycophorin A or high molecular weight hyaluronic acid (HMW-HA) followed by FcɛRI-dependent stimulation has an inhibitory effect on mast cell degranulation. SIGLEC9 gene disruption by CRISPR/Cas9 editing resulted in a significant reduction in Siglec-9 expression in LAD2 cells that also became impervious to inhibition by Siglec-9 agonists. Together, our data shows that human mast cells express Siglec-9 and that engaging this inhibitory receptor can reduce mast cell degranulation.

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Schmassmann, Philip, Tomás A. Martins, Michal Stanczak, Marie-Françoise Ritz, Tala Shekarian, Marta McDaid, Heinz Läubli, and Gregor Hutter. "EXTH-45. MICROGLIA-SPECIFIC DISRUPTION OF SIALIC ACID-SIGLEC-9/E INTERACTIONS: A NOVEL IMMUNOTHERAPY AGAINST GLIOBLASTOMA?" Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi173. http://dx.doi.org/10.1093/neuonc/noab196.684.

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Abstract Recently, ‘don’t eat me’-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as monocyte-derived macrophages (MDM) or microglia (MG). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in MG-centered immunotherapy against GBM. TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Siglec-E blockade increased murine MG mediated GBM cell in vitro phagocytosis (normalized phagocytosis of 1.00 in isotype vs. 1.76 in anti-Siglec-E antibody, p < 0.001). By employing a CT-2A orthotopic GBM mouse model with MG-specific spatio-temporal deletion of Siglece (Sall1 CreERT2 x Siglece flox ), we observed high MG-proliferation upon Siglec-E knockdown (Ki-67+ MG 14.8% in Cre- vs. 34.9% in Cre+, p < 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Cre- vs. 12.3% in Cre+, p < 0.001). This beneficial response was counteracted by an accentuated influx of pro-tumorigenic MDM in the Cre+ group (CD163high CD86low MDM of total MDM 47.1% in Cre- vs. 65.3% in Cre+, p = 0.002), which prevented an efficient adaptive anti-tumor immune response and survival benefit. Currently, we are investigating the cross-talk between GBM-associated MG and MDM upon Siglec-E knockdown by scRNAseq of the tumor-infiltrating immune compartment, including TCR-clonotype tracking. By genetically targeting sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), we observed a strong innate and adaptive immune response with less exhausted tumor-infiltrating CD8+ T-cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003), which resulted in a prolonged survival (30d in WT vs. 41d post-tumor-injection in GNE-KO, p = 0.03). These data identify the sialic-acid-Siglec-E pathway as an anti-phagocytic signal in a pre-clinical GBM model, and demonstrate its therapeutic potential in GBM immunotherapy.

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Schmassmann, P., J. Roux, T. A. Martins, M. Ritz, T. Shekarian, M. McDaid, and H. Läubli G. Hutter. "PL02.2.A Microglia-specific disruption of sialic acid-Siglec-9/E interactions. A novel immunotherapy against glioblastoma?" Neuro-Oncology 24, Supplement_2 (September 1, 2022): ii2. http://dx.doi.org/10.1093/neuonc/noac174.005.

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Abstract Background Recently, ‘don’t eat me’-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as monocyte-derived macrophages (MdM) or microglia (MG). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in MG-centered immunotherapy against GBM. Material and Methods We employed a CT-2A orthotopic GBM mouse model with MG specific (Sall1CreERT2 x Sigleceflox) and whole innate-compartment (Cx3cr1CreERT2 x Sigleceflox) spatio-temporal deletion of Siglece. We applied multi-color flow cytometry, transcriptomics and proteomics analysis to decipher the immune response upon Siglece knockout. Results TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Siglec-E blockade increased murine MG mediated GBM cell in vitro phagocytosis (normalized phagocytosis of 1.00 in isotype vs. 1.76 in anti-Siglec-E antibody, p < 0.001). In the MG specific spatio-temporal deletion of Siglece (Sall1CreERT2 xSigleceflox), we observed high MG-proliferation upon Siglec-E knockout (Ki-67+ MG 14.8% in Cre- vs. 34.9% in Cre+, p < 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Cre- vs. 12.3% in Cre+, p < 0.001). By extending the Siglece knockout to the MdM compartment in our glioma mouse model (Cx3cr1CreERT2 x Sigleceflox) we observed a significantly prolonged survival in the Cx3cr1Cre+ population (21d in Cre- vs. 27d post-tumor injection in Cre+, p = 0.018), which could be further promoted by combining Siglece knockout with CD47 blockade (30d post-tumor injection in Cre+ + anti-CD47). Unbiased proteomics analysis revealed increased antigen processing and presentation capabilities of Siglece knockout MdMs which was confirmed by ex-vivo OT-1 cross-presentation assays. This bridging of innate and adaptive responses with increased T cell priming upon MdM Siglece knockout was further promoted by addition of anti-PD1 antibody to the combined Siglece knockout and anti-CD47 treatment arm. Animals harboring CT-2A tumors, exhibited a sustained survival benefit under the triple therapy, with 23% of animals experiencing long-term remission, even after tumor re-challenge into the contra-lateral hemisphere. By genetically targeting sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), we observed a strong innate and adaptive immune response with increased GBM-cell phagocytosis by MG and MdMs and less exhausted tumor-infiltrating CD8+ T-cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003). Conclusion These data identify the sialic-acid-Siglec-E pathway as an anti-phagocytic signal in a pre-clinical GBM model, and demonstrate its therapeutic potential in GBM immunotherapy.

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Mitic, N., B. Milutinovic, and M. Jankovic. "Assessment of Sialic Acid Diversity in Cancer- and Non-Cancer Related CA125 Antigen Using Sialic Acid-Binding Ig-Like Lectins (Siglecs)." Disease Markers 32, no. 3 (2012): 187–94. http://dx.doi.org/10.1155/2012/309203.

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This study was aimed at obtaining insight into the diversity of sialic acids in cancer- and non-cancer-related CA125 antigen, tumour marker of serous ovarian cancer. Starting from available data suggesting the possible relevance of sialic acids for discriminating CA125 antigens of different origin, we have employed a new experimental approach based on the use of human sialic acid-binding Ig-like lectins, Siglecs, as tools for the investigation of sialylation.Siglec−2, belonging to the group of evolutionarily conserved Siglecs, and Siglec−3, −6, −7, −9 and −10, which are CD33-like Siglecs, were probed in solid-phase binding assays with cancer-related CA125 antigens from pleural fluid of patients with ovarian carcinoma (pfCA125), the OVCAR-3 ovarian carcinoma cell line (clCA125) and a non-cancer-related CA125 antigen, i.e. pregnancy-associated pCA125 antigen.All Siglecs used showed detectable binding to pCA125 antigen. Siglec−3, Siglec−7 and Siglec−2 exhibited moderately stronger binding to pCA125 antigen than the others. In contrast to this, Siglec−2 and Siglec−3 preferentially recognized pfCA125 with greater total binding than for pCA125, whereas Siglec−9 and Siglec−10 were highly selective for clCA125.Siglecs promise to be powerful tools for discriminating CA125 of different origin and could propagate further research on other molecular markers of biomedical and diagnostic importance.

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Schmassmann, Philip, Julien Roux, Nazanin Tatari, Tomas A. Martins, Marie-Françoise Ritz, Tala Shekarian, Heinz Laeubli, and Gregor Hutter. "EXTH-26. MICROGLIA-SPECIFIC DISRUPTION OF SIALIC ACID-SIGLEC-9/E INTERACTIONS: A NOVEL IMMUNOTHERAPY AGAINST GLIOBLASTOMA?" Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii215. http://dx.doi.org/10.1093/neuonc/noac209.825.

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Abstract Recently, ‘don’t eat me’-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as microglia (MG) or monocyte-derived cells (MdCs). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in innate-centered immunotherapy against GBM. TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Using a CT-2A orthotopic GBM mouse model with MG-specific spatio-temporal deletion of Siglece (Sall1CreERT2 x Sigleceflox) , we observed high MG-proliferation upon Siglece knockout (Ki-67+ MG 14.8% in Crenegvs. 34.9% in Creposp < 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Crenegvs. 12.3% in Crepos, p < 0.001). By extending the Siglece knockout to the MdC compartment (Cx3cr1CreERT2x Sigleceflox) we observed a significantly prolonged survival in the Crepospopulation (21d in Crenegvs. 27d post-tumor injection in Crepos, p = 0.018), which could be further promoted by combining Siglece knockout with CD47 blockade (11% long-term remission in Crepos+ anti-CD47). Proteomics analysis revealed increased antigen processing and presentation capabilities of SigleceKOMdCs which was confirmed by ex-vivo OT-1 cross-presentation assays. This increased T cell priming upon MdC SigleceKOwas further boosted by addition of anti-PD1 antibody to the SigleceKO+ anti-CD47 combination. Resulting in 23% of animals experiencing long-term remission in the triple treatment arm, even after tumor re-challenge. Genetic targeting of sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), resulted in increased GBM-cell phagocytosis by MG and MdCs and less exhausted tumor-infiltrating CD8+ T cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003). In a translational approach, we are currently testing anti-Siglec-9 treatment regimens in patient GBM explants, cultured for 5 days in perfusion bioreactors.

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Ibarlucea-Benitez, Itziar, Polina Weitzenfeld, Patrick Smith, and Jeffrey V. Ravetch. "Siglecs-7/9 function as inhibitory immune checkpoints in vivo and can be targeted to enhance therapeutic antitumor immunity." Proceedings of the National Academy of Sciences 118, no. 26 (June 21, 2021): e2107424118. http://dx.doi.org/10.1073/pnas.2107424118.

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Given the role of myeloid cells in T cell activation and in the antitumor response, targeting checkpoint molecules expressed on this population represents a promising strategy to augment antitumor immunity. However, myeloid checkpoints that can be effectively used as immunotherapy targets are still lacking. Here, we demonstrate the therapeutic potential of targeting the myeloid receptors Siglec-7 and Siglec-9 in vivo. By using a humanized immunocompetent murine model, we demonstrate that human Siglec-7 and Siglec-9, in addition to the murine homolog Siglec-E, inhibit the endogenous antitumor immune response, as well as the response to tumor-targeting and immune checkpoint inhibiting antibodies in vivo. The impact of these Siglecs on tumor progression is highly dependent on the anatomical distribution of the tumor and, as a consequence, the local tumor microenvironment, as tumors with a more immune-suppressive tumor microenvironment are less sensitive to Siglec perturbation. Finally, to assess the potential of these two receptors as targets for immunotherapy, we developed Fc engineered blocking antibodies to Siglec-7 and Siglec-9 and demonstrate that Siglec-7 and Siglec-9 blockade can significantly reduce tumor burden in vivo, demonstrating the therapeutic potential of targeting these two receptors.

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Attrill, Helen, Hirokazu Takazawa, Simone Witt, Soerge Kelm, Rainer Isecke, Reinhard Brossmer, Takayuki Ando, et al. "The structure of siglec-7 in complex with sialosides: leads for rational structure-based inhibitor design." Biochemical Journal 397, no. 2 (June 28, 2006): 271–78. http://dx.doi.org/10.1042/bj20060103.

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Siglecs (sialic acid binding Ig-like lectins) are transmembrane receptors for sialylated glycoconjugates that modulate cellular interactions and signalling events in the haematopoietic, immune and nervous systems. Siglec-7 is a structural prototype for the recently described family of immune inhibitory CD33-related siglecs and is predominantly expressed on natural killer cells and monocytes, as well as subsets of CD8 T-cells. Siglec-specific inhibitors are desired for the detection of masked and unmasked forms of siglecs, to aid in dissection of signalling pathways and as tools to investigate siglecs as potential therapeutic targets. As a first step towards this end, we present the crystal structure of siglec-7 in complex with a sialylated ligand, the ganglioside analogue DSLc4 [α(2,3)/α(2,6) disialyl lactotetraosyl 2-(trimethylsilyl)ethyl], which allows for a detailed description of the binding site, required for structure-guided inhibitor design. Mutagenesis and binding assays were used to demonstrate a key structural role for Lys131, a residue that changes conformation upon sialic acid binding. Differences between the binding sites of siglec family members were then exploited using α-methyl Neu5Ac (N-acetylneuraminic acid) as a basic scaffold. A co-crystal of siglec-7 in complex with the sialoside inhibitor, oxamido-Neu5Ac [methyl α-9-(amino-oxalyl-amino)-9-deoxy-Neu5Ac] and inhibition data for the sialosides gives clear leads for future inhibitor design.

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Pegon, Julie N., Cécile V. Denis, Soline Odouard, Olivier D. Christophe, and Peter J. Lenting. "Siglecs as Novel Cellular Partners for Von Willebrand Factor." Blood 116, no. 21 (November 19, 2010): 4306. http://dx.doi.org/10.1182/blood.v116.21.4306.4306.

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Abstract Abstract 4306 Introduction: Von Willebrand factor (VWF) is a multimeric protein that is pertinent to the haemostatic process by promoting platelet recruitment to the growing thrombus and acting as a carrier-protein for factor VIII. It is well established that VWF is able to interact with several cellular receptors present on the surface of platelets and leukocytes. In search for novel cellular partners for VWF present on these cells, we made use of the notion that VWF is heavily glycosylated, with the mature molecule containing 12 N-linked glycans and 10 O-linked glycans. Importantly, the vast majority of these glycans (>90%) are sialylated. The human proteome contains a family of sialic acid-binding receptors, known as Sialic acid-binding Immunoglobulin-like Lectins (Siglecs), which are expressed on cells of hematopoietic origin. The current study was designed to investigate the potential of Siglecs to interact with VWF. Methods: Stable human HEK293 cell lines were established that express human Siglec-5, Siglec-7 or Siglec-9. In addition, soluble variants of Siglecs were obtained: monomeric HPC4-tagged Siglec-5 and Siglec-7 (sSg5/HPC4 & sSg7/HPC4) and dimeric Fc-fusion proteins for human Siglec-3, -5, -7, -9, -10, -11 and murine Siglec-F (sSg-3/Fc etc). These Siglecs were used to study their interaction with purified plasma-derived (pdVWF) or recombinant BHK-cell derived VWF (rVWF). Protein-protein interactions were investigated via immuno-sorbent assays and via surface plasmon resonance (SPR) using Octet QK equipment. Binding of VWF to Siglec-expressing cells was assessed via immuno-fluorescence microscopy. Results: We observed consistent association of VWF (irrespective whether immuno-sorbent or SPR assays were used) to all of the immobilized Siglecs tested, with the exception of sSg-11/Fc that did not interact with pdVWF or with rVWF. Inversely, all soluble Siglecs but sSg-11/Fc efficiently bound to immobilized pdVWF or rVWF. Half-maximal binding in immuno-sorbent assays was between 97 and 645 nM (binding of VWF to immobilized Siglecs) versus 166 and 270 nM (binding of Siglecs to immobilized VWF). More detailed studies on the determination of the kinetic parameters using SPR technology are in progress. Specificity of the interaction was confirmed by treating VWF with sialidase before testing Siglec binding, and such treatment resulted in a strongly reduced (up to 80%) ability of Siglecs to bind to immobilized VWF. VWF was further found to bind to Siglec-5, -7 or -9 expressing HEK293 cells as assessed via immuno-fluorescence microscopy. In general, 10–15 % of the Siglec-expressing cells were covered with VWF after incubation, with the fluorescent intensity increasing dose-dependently with the applied VWF concentration. No fluorescent signal was observed upon incubation of VWF with non-transfected cells or when VWF was omitted from the incubation. Since Siglecs may be masked by the presence of endogenous sialylated proteins at the cellular surface, we also tested VWF binding to these cells following sialidase treatment. Sialidase treatment of cells resulted in a marked increase in the number of VWF-binding cells (up to 80% of the Siglec-positive cells) as well as an increase in intensity of the fluorescent signal. Co-localization of VWF with Siglecs at the cellular surface was confirmed by DuoLink-analysis, which allows the detection of proteins that are in the vicinity of ≤40 nm. Emerging evidence demonstrates that endothelial. Conclusions: We identified one murine and six human Siglec-family members as novel partners for VWF. Interactions between VWF and Siglecs are mediated by sialic acid structures present on VWF. In addition, the cellular accessibility of Siglecs for VWF is modulated by cis-acting sialylated proteins at the cell surface. In conclusion, our data demonstrate that the VWF glycome allows the interaction with a novel family of cellular receptors, potentially opening previously unrecognized avenues in the biology of VWF. Disclosures: No relevant conflicts of interest to declare.

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Virtanen, Helena, Johanna M. U. Silvola, Anu Autio, Xiang-Guo Li, Heidi Liljenbäck, Sanna Hellberg, Riikka Siitonen, et al. "Comparison of 68Ga-DOTA-Siglec-9 and 18F-Fluorodeoxyribose-Siglec-9: Inflammation Imaging and Radiation Dosimetry." Contrast Media & Molecular Imaging 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/7645070.

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Sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) is a ligand of inflammation-inducible vascular adhesion protein-1 (VAP-1). We compared 68Ga-DOTA- and 18F-fluorodeoxyribose- (FDR-) labeled Siglec-9 motif peptides for PET imaging of inflammation. Methods. Firstly, we examined 68Ga-DOTA-Siglec-9 and 18F-FDR-Siglec-9 in rats with skin/muscle inflammation. We then studied 18F-FDR-Siglec-9 for the detection of inflamed atherosclerotic plaques in mice and compared it with previous 68Ga-DOTA-Siglec-9 results. Lastly, we estimated human radiation dosimetry from the rat data. Results. In rats, 68Ga-DOTA-Siglec-9 (SUV, 0.88±0.087) and 18F-FDR-Siglec-9 (SUV, 0.77±0.22) showed comparable (P=0.29) imaging of inflammation. In atherosclerotic mice, 18F-FDR-Siglec-9 detected inflamed plaques with a target-to-background ratio (1.6±0.078) similar to previously tested 68Ga-DOTA-Siglec-9 (P=0.35). Human effective dose estimates for 68Ga-DOTA-Siglec-9 and 18F-FDR-Siglec-9 were 0.024 and 0.022 mSv/MBq, respectively. Conclusion. Both tracers are suitable for PET imaging of inflammation. The easier production and lower cost of 68Ga-DOTA-Siglec-9 present advantages over 18F-FDR-Siglec-9, indicating it as a primary choice for clinical studies.

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Avril, T., H. Attrill, J. Zhang, A. Raper, and P. R. Crocker. "Negative regulation of leucocyte functions by CD33-related siglecs." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1024–27. http://dx.doi.org/10.1042/bst0341024.

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The siglecs (sialic acid-binding Ig-like lectins) are a family of transmembrane receptors expressed in the haemopoietic, immune and nervous systems. The CD33-related siglecs are a distinct subset mostly expressed in the innate immune system where they can function as inhibitory receptors by suppressing the signalling mediated by receptors coupled with ITAMs (immunoreceptor tyrosine-based activation motifs). CD33-related siglecs contain ITIMs (immunoreceptor tyrosine-based inhibitory motifs) that recruit and activate SHP-1 [SH2 (Src homology 2) domain-containing phosphatase-1] and SHP-2. In addition, the ITIMs of CD33-related siglecs can suppress siglec-dependent adhesion of sialylated ligands and mediate endocytosis. Siglec-H is a recently characterized murine CD33-related endocytic receptor that lacks intrinsic tyrosine-based signalling motifs and is expressed selectively on PDCs (plasmacytoid dendritic cells). Siglec-H depends on DAP12 (DNAX-activating protein of 12 kDa) for surface expression and cross-linking with anti-siglec-H antibodies can selectively inhibit interferon-α production by PDCs following TLR9 (Toll-like receptor 9) ligation. Thus CD33-related siglecs are able to mediate diverse inhibitory functions of leucocytes in the innate immune system via both ITIM-dependent and -independent pathways.

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Adeniji, Opeyemi S., Leticia Kuri-Cervantes, Chenfei Yu, Ziyang Xu, Michelle Ho, Glen M. Chew, Cecilia Shikuma, et al. "Siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cells." PLOS Pathogens 17, no. 11 (November 11, 2021): e1010034. http://dx.doi.org/10.1371/journal.ppat.1010034.

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Siglec-9 is an MHC-independent inhibitory receptor expressed on a subset of natural killer (NK) cells. Siglec-9 restrains NK cytotoxicity by binding to sialoglycans (sialic acid-containing glycans) on target cells. Despite the importance of Siglec-9 interactions in tumor immune evasion, their role as an immune evasion mechanism during HIV infection has not been investigated. Using in vivo phenotypic analyses, we found that Siglec-9+ CD56dim NK cells, during HIV infection, exhibit an activated phenotype with higher expression of activating receptors and markers (NKp30, CD38, CD16, DNAM-1, perforin) and lower expression of the inhibitory receptor NKG2A, compared to Siglec-9- CD56dim NK cells. We also found that levels of Siglec-9+ CD56dim NK cells inversely correlate with viral load during viremic infection and CD4+ T cell-associated HIV DNA during suppressed infection. Using in vitro cytotoxicity assays, we confirmed that Siglec-9+ NK cells exhibit higher cytotoxicity towards HIV-infected cells compared to Siglec-9- NK cells. These data are consistent with the notion that Siglec-9+ NK cells are highly cytotoxic against HIV-infected cells. However, blocking Siglec-9 enhanced NK cells’ ability to lyse HIV-infected cells, consistent with the known inhibitory function of the Siglec-9 molecule. Together, these data support a model in which the Siglec-9+ CD56dim NK subpopulation is highly cytotoxic against HIV-infected cells even whilst being restrained by the inhibitory effects of Siglec-9. To harness the cytotoxic capacity of the Siglec-9+ NK subpopulation, which is dampened by Siglec-9, we developed a proof-of-concept approach to selectively disrupt Siglec/sialoglycan interactions between NK and HIV-infected cells. We achieved this goal by conjugating Sialidase to several HIV broadly neutralizing antibodies. These conjugates selectively desialylated HIV-infected cells and enhanced NK cells’ capacity to kill them. In summary, we identified a novel, glycan-based interaction that may contribute to HIV-infected cells’ ability to evade NK immunosurveillance and developed an approach to break this interaction.

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Delaveris, Corleone S., Shannon H. Chiu, Nicholas M. Riley, and Carolyn R. Bertozzi. "Modulation of immune cell reactivity with cis-binding Siglec agonists." Proceedings of the National Academy of Sciences 118, no. 3 (January 11, 2021): e2012408118. http://dx.doi.org/10.1073/pnas.2012408118.

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Inflammatory pathologies caused by phagocytes lead to numerous debilitating conditions, including chronic pain and blindness due to age-related macular degeneration. Many members of the sialic acid-binding immunoglobulin-like lectin (Siglec) family are immunoinhibitory receptors whose agonism is an attractive approach for antiinflammatory therapy. Here, we show that synthetic lipid-conjugated glycopolypeptides can insert into cell membranes and engage Siglec receptors in cis, leading to inhibitory signaling. Specifically, we construct a cis-binding agonist of Siglec-9 and show that it modulates mitogen-activated protein kinase (MAPK) signaling in reporter cell lines, immortalized macrophage and microglial cell lines, and primary human macrophages. Thus, these cis-binding agonists of Siglecs present a method for therapeutic suppression of immune cell reactivity.

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Carlin, Aaron F., Satoshi Uchiyama, Yung-Chi Chang, Amanda L. Lewis, Victor Nizet, and Ajit Varki. "Molecular mimicry of host sialylated glycans allows a bacterial pathogen to engage neutrophil Siglec-9 and dampen the innate immune response." Blood 113, no. 14 (April 2, 2009): 3333–36. http://dx.doi.org/10.1182/blood-2008-11-187302.

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Abstract Human neutrophil Siglec-9 is a lectin that recognizes sialic acids (Sias) via an amino-terminal V-set Ig domain and possesses tyrosine-based inhibitory motifs in its cytoplasmic tail. We hypothesized that Siglec-9 recognizes host Sias as “self,” including in cis interactions with Sias on the neutrophil's own surface, thereby dampening unwanted neutrophil reactivity. Here we show that neutrophils presented with immobilized multimerized Siaα2-3Galβ1-4GlcNAc units engage them in trans via Siglec-9. The sialylated capsular polysaccharide of group B Streptococcus (GBS) also presents terminal Siaα2-3Galβ1-4GlcNAc units, and similarly engages neutrophil Siglec-9, dampening neutrophil responses in a Sia- and Siglec-9–dependent manner. Reduction in the neutrophil oxidative burst, diminished formation of neutrophil extracellular DNA traps, and increased bacterial survival are also facilitated by GBS sialylated capsular polysaccharide interactions with Siglec-9. Thus, GBS can impair neutrophil defense functions by coopting a host inhibitory receptor via sialoglycan molecular mimicry, a novel mechanism of bacterial immune evasion.

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Wen, Ru M., Jessica C. Stark C. Stark, Fernando García-Marqués, Hongjuan Zhao, Rosie Nolley, Carolyn R. Bertozzi, Sharon J. Pitteri, and James D. Brooks. "Abstract A13: Siglec-7/9-sialic acid interactions inhibit T cell immune response in prostate cancer." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): A13. http://dx.doi.org/10.1158/2326-6074.tumimm22-a13.

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Abstract Immunotherapy has rapidly expanded in the care of patients with cancer with the discovery of immune checkpoints like PD-1 and CTLA-4. However, current immune checkpoint inhibitors are largely ineffective for prostate cancer. Recent studies suggest an alternative immune evasion pathway through the interactions between Sialic acid-binding immunoglobulin-type lectin proteins (Siglec) and their ligands, sialylated glycoprotein. Siglec-7/9-sialic acid interactions are reported to inhibit the immune cell response in several cancer types including leukemia, melanoma, and non-small cell lung cancer. Here, we demonstrated that Siglec-7/9 ligands were expressed in both prostate cancer tumor tissues and cell lines. We promoted T cell-mediated cytotoxicity of cancer cells by disrupting the interactions between Siglec-7/9 and their ligands. We discovered that FXYD5 and CD59 are potential Siglec-7 and Siglec-9 ligands, respectively, with CRISPRi screen. We then found that FXYD5 and CD59 knockout cells had reduced Siglec-7/9 binding capacity and enhanced T cells mediated killing effects on prostate cancer cells. These results provide a rationale for novel immune checkpoints and potential approaches for targeting Siglec-7/FXYD5 and Siglec-9/CD59 immune checkpoints for prostate cancer. Citation Format: Ru M Wen, Jessica C. Stark C Stark, Fernando García-Marqués, Hongjuan Zhao, Rosie Nolley, Carolyn R Bertozzi, Sharon J Pitteri, James D. Brooks. Siglec-7/9-sialic acid interactions inhibit T cell immune response in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A13.

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Daly, John, Subhashis Sarkar, Alessandro Natoni, Robert Henderson, Dawn Swan, Mattias Carlsten, and Michael E. O'Dwyer. "Hypersialylation Protects Multiple Myeloma Cells from NK Cell-Mediated Immunosurveillance and This Can be Overcome By Targeted Desialylation Using a Sialyltransferase Inhibitor." Blood 134, Supplement_1 (November 13, 2019): 138. http://dx.doi.org/10.1182/blood-2019-126613.

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Introduction: Evading Natural Killer (NK) cell-mediated immunosurveillance is key to the development of Multiple Myeloma (MM). Recent attention has focused on the role of hypersialylation in facilitating immune-evasion of NK cells. Abnormal cell surface sialylation is considered a hallmark of cancer and we have implicated hypersialylation in MM disease progression. Certain sialylated glycans can act as ligands for the sialic acid-binding immunoglobulin-like lectin (Siglec) receptors expressed by NK cells (Siglec-7 and Siglec-9). These ITIM motif-containing inhibitory receptors transmit an inhibitory signal upon sialic acid engagement. We hypothesized that desialylation of MM cells or targeted interruption of Siglec expression could lead to enhanced NK cell mediated cytotoxicity of MM cells. Methodology: MM cells were treated with the sialidase neuraminidase prior to co-culture with primary NK (PNK) cells. MM cells were treated with 300µM 3Fax-Neu5Ac (sialyltransferase inhibitor) for 3 days prior to co-cultures with PNK cells. PNK cells were expanded, IL-2 activated (500U/ml) overnight, or naïve (resting). Primary MM samples/MM cell lines were screened with Siglec-7/9 chimeras (10µg/ml). PNK (IL-2 activated) cells were stained with anti-Siglec-7 and anti-Siglec-9 antibodies. Siglec-7 was targeted for knockout (KO) using the CRISPR/Cas9 system, a pre-designed guideRNA and the MaxCyteGT transfection system. MM cells were treated with 10µg/ml of Daratumumab prior to co-culture with expanded PNK cells. Results: Using recombinant Siglec-7/9 chimeras a panel of MM cell lines (MM1S, RPMI-8226, H929, JJN3 and U266) were shown to express ligands for Siglec-7 and Siglec-9 (>85%, n=3). Primary MM cells isolated from BM of newly diagnosed (n=3) and relapsed patients (n=2) were also shown to express Siglec-7 ligands (72.5±17.5%, 36.5% respectively). PNK cells express Siglec-7 and Siglec-9 (94.3±3.3% and 61±8.8% respectively, n=6). Desialylation of the MM cell lines JJN3 and H929 using neuraminidase significantly enhanced killing of MM cells by healthy donor (HD) derived PNK cells (expanded, IL-2 activated and naïve, n=7) at multiple effector:target (E:T) cell ratios. Furthermore, de-sialylation of JJN3 and H929 using neuraminidase resulted in increased NK cell degranulation (CD107α expression), compared to a glycobuffer control (n=7). De-sialylation, using 300µM 3Fax-Neu5Ac, resulted in strongly enhanced killing of MM1S by expanded HD-derived PNK cells at multiple E:T ratios (n=5, p<0.01 at 0.5:1, p<0.001 at 1:1, p<0.01 at 2.5:1). Furthermore, CD38 expression on H929 MM cells significantly increased after treatment with 300µM 3Fax-Neu5Ac for 3 days (p<0.01, n=3). In a cytotoxicity assay, expanded PNK cell-mediated antibody dependent cellular cytotoxicity (ADCC) of H929 MM cells pre-treated with Daratumumab (anti-CD38 moAb) and 3Fax-Neu5Ac was significantly higher than H929 cells pre-treated with Dara (p<0.05 at 0.5:1, p<0.01 at 1:1) or 3Fax-Neu5Ac (p<0.01 at 0.5:1, p<0.01 at 1:1) alone (n=5). Using CRISPR/Cas9, over 50% complete KO of Siglec-7 was observed on expanded PNK cells, yet did not result in enhanced NK cell-mediated cytotoxicity against either H929 or JJN3 (n=7). Siglec-9 KO using CRISPR/Cas9 is ongoing. Discussion: Hypersialylation of MM cells facilitates immune evasion and targeted removal of sialic acid strongly enhances the cytotoxicity of NK cells against MM. However, to date the role of Siglecs remains inconclusive. Nevertheless, our data suggest that targeted desialylation is a novel therapeutic strategy worth exploring in MM. In particular, upregulation of CD38 provides a strong rationale for combinatory strategies employing targeted desialylation with CD38 moAbs such as Daratumumab, with the goal of maximizing ADCC. Disclosures Sarkar: Onkimmune: Research Funding. O'Dwyer:Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; GlycoMimetics Inc: Research Funding; AbbVie: Consultancy.

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Schleimer, Robert P., Ronald L. Schnaar, and Bruce S. Bochner. "Regulation of airway inflammation by Siglec-8 and Siglec-9 sialoglycan ligand expression." Current Opinion in Allergy and Clinical Immunology 16, no. 1 (February 2016): 24–30. http://dx.doi.org/10.1097/aci.0000000000000234.

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Chrusciel, Paulina, Emrah Yatkin, Xiang-Guo Li, Ulla-Marjut Jaakkola, Juhani Knuuti, Sirpa Jalkanen, and Anne Roivainen. "Safety Study of Single-Dose Intravenously Administered DOTA-Siglec-9 Peptide in Sprague Dawley Rats." International Journal of Toxicology 38, no. 1 (January 2019): 4–11. http://dx.doi.org/10.1177/1091581818821606.

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The peptide-based radioactive compound [68Ga]Ga-DOTA-Siglec-9 is a novel agent for imaging of inflammation with positron emission tomography. The drug target of [68Ga]Ga-DOTA-Siglec-9 is vascular adhesion protein 1. Previous studies have obtained promising results with [68Ga]Ga-DOTA-Siglec-9 in experimental animals. However, before taking this novel imaging agent into clinical trials, safety and toxicological studies need to be performed with the nonradioactive precursor compound DOTA-Siglec-9. This extended single-dose toxicity study was designed to provide information on the major toxic effects of DOTA-Siglec-9 and to indicate possible target organs after a single intravenous (iv) injection in rats. The study was performed using 60 adult Hsd: Sprague Dawley rats and included a control group and a treatment group to investigate the toxicity of DOTA-Siglec-9 solution at a final concentration of 0.2 mg/mL after a single iv injection of 582 µg/kg. The maximum dose tested was 1,000-fold the clinical dose on a mg/kg basis as indicated in European Medicines Agency International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guideline M3(R2). The planned human clinical dose is approximately 0.582 µg of DOTA-Siglec-9 per kg of body mass. This study demonstrates that iv administration of DOTA-Siglec-9 at a dose of 582 µg/kg was well tolerated in rats and did not produce toxicologically significant adverse effects.

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18

Cao, Ling, and Xiaoliang Yuan. "Research progress on the role of sialic acid-binding immunoglobulin-like lectin 9 in various diseases." Trends in Immunotherapy 5, no. 2.1 (October 8, 2021): 51. http://dx.doi.org/10.24294/ti.v5.i2.1.1366.

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Sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) is a receptor that expresses on the surface of immune cells. It plays an important role in the body’s immune response. Increased expression of Siglec-9 has been reported in infectious diseases, autoimmune diseases and cancer. Pathogenic microorganism and tumor cells can inhibit the recognition and killing of immune cells by upregulating their own specific sialic acid and binding with Siglec-9 on the surface of host immune cells, and suppress the release of pro-inflammatory cytokines and promote the release of anti-inflammatory cytokines, eventually leading to immunosuppression, tumor immune escape and the like. However, the immunosuppressive function of Siglec-9 may be advantageous for diseases such as neutrophil asthma and autoimmune diseases. Therefore, further research on the mechanism of action of Siglec-9 is of great significance.

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YU, Zhenbao, Meryem MAOUI, Liangtang WU, Denis BANVILLE, and Shi-Hsiang SHEN. "mSiglec-E, a novel mouse CD33-related siglec (sialic acid-binding immunoglobulin-like lectin) that recruits Src homology 2 (SH2)-domain-containing protein tyrosine phosphatases SHP-1 and SHP-2." Biochemical Journal 353, no. 3 (January 25, 2001): 483–92. http://dx.doi.org/10.1042/bj3530483.

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The sialic acid-binding immunoglobulin-like lectins (siglecs) represent a recently defined distinct subset of the immunoglobulin superfamily. By using the Src homology 2 (SH2)-domain-containing protein tyrosine phosphatase SHP-1 as bait in a yeast two-hybrid screen, we have identified a new member of the mouse siglec family, mSiglec-E. The mSiglec-E cDNA encodes a protein of 467 amino acids that contains three extracellular immunoglobulin-like domains, a transmembrane region and a cytoplasmic tail bearing two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). mSiglec-E is highly expressed in mouse spleen, a tissue rich in leucocytes. The ITIMs of mSiglec-E can recruit SHP-1 and SHP-2, two inhibitory regulators of immunoreceptor signal transduction. This suggests that the function of mSiglec-E is probably an involvement in haematopoietic cells and the immune system as an inhibitory receptor. When expressed in COS-7 cells, mSiglec-E was able to mediate sialic acid-dependent binding to human red blood cells, suggesting that mSiglec-E may function through cell–cell interactions. In comparison with the known members of the siglec family, mSiglec-E exhibits a high degree of sequence similarity to both human siglec-7 and siglec-9. The gene encoding mSiglec-E is localized in the same chromosome as that encoding mouse CD33. Phylogenetic analysis reveals that neither mouse mSiglec-E nor CD33 shows a clear relationship with any human siglecs so far identified.

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20

Yu, Huifeng, Anabel Gonzalez-Gil, Yadong Wei, Steve M. Fernandes, Ryan N. Porell, Katarina Vajn, James C. Paulson, Corwin M. Nycholat, and Ronald L. Schnaar. "Siglec-8 and Siglec-9 binding specificities and endogenous airway ligand distributions and properties." Glycobiology 27, no. 7 (May 4, 2017): 657–68. http://dx.doi.org/10.1093/glycob/cwx026.

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21

von Gunten, Stephan, Shida Yousefi, Michael Seitz, Stephan M. Jakob, Thomas Schaffner, Reinhard Seger, Jukka Takala, Peter M. Villiger, and Hans-Uwe Simon. "Siglec-9 transduces apoptotic and nonapoptotic death signals into neutrophils depending on the proinflammatory cytokine environment." Blood 106, no. 4 (August 15, 2005): 1423–31. http://dx.doi.org/10.1182/blood-2004-10-4112.

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Abstract We report about new apoptotic and non-apoptotic death pathways in neutrophils that are initiated via the surface molecule sialic acid-binding immunoglobulin-like lectin (Siglec)-9. In normal neutrophils, Siglec-9 ligation induced apoptosis. Inflammatory neutrophils obtained from patients with acute septic shock or rheumatoid arthritis demonstrated increased Siglec-9, but normal Fas receptor-mediated cytotoxic responses when compared with normal blood neutrophils. The increased Siglec-9-mediated death was mimicked in vitro by short-term preincubation of normal neutrophils with proinflammatory cytokines, such as granulocyte/macrophage colony-stimulating factor (GM-CSF), interferon-α (IFN-α), and IFN-γ, and was demonstrated to be caspase independent. Experiments using scavengers of reactive oxygen species (ROS) or neutrophils unable to generate ROS indicated that both Siglec-9-mediated caspase-dependent and caspase-independent forms of neutrophil death depend on ROS. Interestingly, the caspase-independent form of neutrophil death was characterized by cytoplasmic vacuolization and several other nonapoptotic morphologic features, which were also seen in neutrophils present in joint fluids from rheumatoid arthritis patients. Taken together, these data suggest that apoptotic (ROS- and caspase-dependent) and nonapoptotic (ROS-dependent) death pathways are initiated in neutrophils via Siglec-9. The new insights have important implications for the pathogenesis, diagnosis, and treatment of inflammatory diseases such as sepsis and rheumatoid arthritis. (Blood. 2005;106:1423-1431)

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Ikehara, Yuzuru, Sanae Kabata Ikehara, and James C. Paulson. "Negative Regulation of T Cell Receptor Signaling by Siglec-7 (p70/AIRM) and Siglec-9." Journal of Biological Chemistry 279, no. 41 (August 3, 2004): 43117–25. http://dx.doi.org/10.1074/jbc.m403538200.

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23

Jia, Yi, Huifeng Yu, Steve M. Fernandes, Yadong Wei, Anabel Gonzalez-Gil, Mary G. Motari, Katarina Vajn, et al. "Expression of ligands for Siglec-8 and Siglec-9 in human airways and airway cells." Journal of Allergy and Clinical Immunology 135, no. 3 (March 2015): 799–810. http://dx.doi.org/10.1016/j.jaci.2015.01.004.

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24

Chen, Zi, Fang-Fang Bai, Lu Han, Jin Zhu, Tao Zheng, Zhou Zhu, and Lin-Fu Zhou. "Targeting Neutrophils in Severe Asthma via Siglec-9." International Archives of Allergy and Immunology 175, no. 1-2 (2018): 5–15. http://dx.doi.org/10.1159/000484873.

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25

Jødal, Lars, Anne Roivainen, Vesa Oikonen, Sirpa Jalkanen, Søren B. Hansen, Pia Afzelius, Aage K. O. Alstrup, Ole L. Nielsen, and Svend B. Jensen. "Kinetic Modelling of [68Ga]Ga-DOTA-Siglec-9 in Porcine Osteomyelitis and Soft Tissue Infections." Molecules 24, no. 22 (November 13, 2019): 4094. http://dx.doi.org/10.3390/molecules24224094.

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Background: [68Ga]Ga-DOTA-Siglec-9 is a positron emission tomography (PET) radioligand for vascular adhesion protein 1 (VAP-1), a protein involved in leukocyte trafficking. The tracer facilitates the imaging of inflammation and infection. Here, we studied the pharmacokinetic modelling of [68Ga]Ga-DOTA-Siglec-9 in osteomyelitis and soft tissue infections in pigs. Methods: Eight pigs with osteomyelitis and soft tissue infections in the right hind limb were dynamically PET scanned for 60 min along with arterial blood sampling. The fraction of radioactivity in the blood accounted for by the parent tracer was evaluated with radio-high-performance liquid chromatography. One- and two-tissue compartment models were used for pharmacokinetic evaluation. Post-mortem soft tissue samples from one pig were analysed with anti-VAP-1 immunofluorescence. In each analysis, the animal’s non-infected left hind limb was used as a control. Results: Tracer uptake was elevated in soft tissue infections but remained low in osteomyelitis. The kinetics of [68Ga]Ga-DOTA-Siglec-9 followed a reversible 2-tissue compartment model. The tracer metabolized quickly; however, taking this into account, produced more ambiguous results. Infected soft tissue samples showed endothelial cell surface expression of the Siglec-9 receptor VAP-1. Conclusion: The kinetics of [68Ga]Ga-DOTA-Siglec-9 uptake in porcine soft tissue infections are best described by the 2-tissue compartment model.

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26

Nalle, Sam, Helen Lam, Cheryl Barner, Hua Long, Spencer Liang, Arnon Rosenthal, and Daniel Maslyar. "Abstract 613: AL009 is a multi-Siglec inhibitor engineered to bind myeloid cells that enhances innate and adaptive immunity to cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 613. http://dx.doi.org/10.1158/1538-7445.am2022-613.

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Abstract Background - Inhibitory sialic acid-binding immunoglobulin-type lectins (Siglecs) are a subset of the Siglec family of cell surface receptors that potentiate immune tolerance. A multitude of inhibitory Siglecs on myeloid cells become engaged in sialic acid-rich tumor microenvironments, suggesting that disrupting Siglec-sialic acid signaling could confer therapeutic benefit in cancer. To accomplish this, we designed AL009, an engineered Siglec-9 extracellular domain-Fc fusion molecule that acts as a sialic acid trap and a multi-Siglec inhibitor, repolarizing suppressive myeloid cells and activating an anti-cancer response. Methods - Cooperative binding of AL009 was analyzed by flow cytometry using cultured human tumor cell lines and myeloid-derived suppressor cells (MDSCs) differentiated from primary human monocytes. Monocytes, MDSCs, and macrophages differentiated from primary human monocytes were assessed for AL009 binding by flow cytometry. AL009m (AL009 with a mouse Fc) was fluorophore-labeled and intravenously injected into B6 mice to analyze biodistribution via ex vivo tissue imaging over time. Initial toxicology screening was conducted in cynomolgus monkeys in a non-terminal study. Results - AL009 displays cooperative binding with sialic acid and Fc gamma receptors on myeloid cells. When comparing binding among myeloid cell subsets, AL009 preferentially binds MDSCs. Analysis of the biodistribution of labeled AL009m in mice showed the greatest accumulation in the spleen, consistent with immune cell targeting in vivo. Further, Fc engineering of AL009 improved the pharmacodynamic profile compared to a non-engineered Fc. In cynomolgus monkeys, single doses of 80 mg/kg appeared safe and without clinically significant findings. Conclusions - The engineered structure of AL009 leads to preferential binding to an immunosuppressive subset of myeloid cells. This targeting leads to repolarization of myeloid cells and activates an innate and adaptive anti-cancer response. Pharmacologically relevant doses of AL009 appear well-tolerated in initial studies in non-human primates, supporting further development for entry into clinical studies. Citation Format: Sam Nalle, Helen Lam, Cheryl Barner, Hua Long, Spencer Liang, Arnon Rosenthal, Daniel Maslyar. AL009 is a multi-Siglec inhibitor engineered to bind myeloid cells that enhances innate and adaptive immunity to cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 613.

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Nalle, Sam, Helen Lam, Ling Leung, Spencer Liang, and Daniel Maslyar. "875 AL009, a fusion protein and multi-Siglec inhibitor, repolarizes suppressive myeloid cells and potentiates anti-cancer effects." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A917. http://dx.doi.org/10.1136/jitc-2021-sitc2021.875.

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BackgroundSialic acid-binding immunoglobulin-type lectins (Siglecs) are a family of cell surface receptors expressed predominantly on myeloid cells that function to promote immune tolerance. Tumors increase the expression of sialic acid glycans and co-opt the immunosuppressive effects of Siglecs, driving tumor resident immune cells toward a cancer permissive phenotype. Due to the overlapping expression profile of Siglec family members on myeloid cells, targeting multiple Siglecs is required for robust efficacy. Here, we present data on AL009, an engineered Siglec-9 extracellular domain-Fc fusion molecule that acts as a sialic acid trap and repolarizes suppressive myeloid cells to activate an anti-cancer immune response.MethodsThe ability of AL009 to competitively block various Siglec-Fc fusion proteins was assessed using cultured human myeloid-derived suppressor cells (MDSCs). MDSC repolarization was analyzed by flow cytometry. MDSCs were co-cultured with activated CD8+ T cells with and without exposure to AL009 and functionally assessed for T-cell activation by flow cytometry and ELISA. In vivo tumor models, including the MC38 and E0771 murine syngeneic subcutaneous models and the B16F10 intravenous lung metastasis model, were used to assess AL009 engineered with a murine Fc (AL009m).ResultsAL009 competitively blocks the ability of at least 5 inhibitory Siglec family members to bind their corresponding sialic acid ligands. When incubated with MDSCs, AL009 promotes CD163 and CD206 downregulation and induces proinflammatory chemokine secretion, consistent with a repolarization effect. Further, AL009 potently relieves MDSC suppression of T cells in a co-culture system. In the MC38 and E0771 murine syngeneic subcutaneous tumor models, AL009m inhibits tumor growth as a monotherapy and in combination with the checkpoint inhibitor anti-PD-L1. In addition, AL009m combines with the tumor antigen targeting antibody TRP-1 in the B16F10 intravenous lung metastasis model to reduce tumor burden.ConclusionsAL009 represents a novel approach to targeting the myeloid cell compartment in oncology by directly repolarizing myeloid cells without cell depletion or limiting the targeting to specific suppressive subpopulations. AL009 has the potential to address tumors that are unresponsive or refractory to standard immunotherapies. These data support further development of AL009 in the clinic with IND enabling studies ongoing.

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Lizcano, Anel, Ismael Secundino, Simon Döhrmann, Ross Corriden, Cristina Rohena, Sandra Diaz, Pradipta Ghosh, Lingquan Deng, Victor Nizet, and Ajit Varki. "Erythrocyte sialoglycoproteins engage Siglec-9 on neutrophils to suppress activation." Blood 129, no. 23 (June 8, 2017): 3100–3110. http://dx.doi.org/10.1182/blood-2016-11-751636.

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29

McMillan, Sarah J., Ritu S. Sharma, Emma J. McKenzie, Hannah E. Richards, Jiquan Zhang, Alan Prescott та Paul R. Crocker. "Siglec-E is a negative regulator of acute pulmonary neutrophil inflammation and suppresses CD11b β2-integrin–dependent signaling". Blood 121, № 11 (14 березня 2013): 2084–94. http://dx.doi.org/10.1182/blood-2012-08-449983.

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Key Points First report describing in vivo function of siglec-E as a negative regulator of neutrophil recruitment in acute lung inflammation. Implications for the human functional ortholog, siglec-9, and its potential role in regulating inflammatory lung disease.

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30

Aalto, Kristiina, Anu Autio, Elina A. Kiss, Kati Elima, Yvonne Nymalm, Tibor Z. Veres, Fumiko Marttila-Ichihara, et al. "Siglec-9 is a novel leukocyte ligand for vascular adhesion protein-1 and can be used in PET imaging of inflammation and cancer." Blood 118, no. 13 (September 29, 2011): 3725–33. http://dx.doi.org/10.1182/blood-2010-09-311076.

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Abstract Leukocyte migration to sites of inflammation is regulated by several endothelial adhesion molecules. Vascular adhesion protein-1 (VAP-1) is unique among the homing-associated molecules as it is both an enzyme that oxidizes primary amines and an adhesin. Although granulocytes can bind to endothelium via a VAP-1–dependent manner, the counter-receptor(s) on this leukocyte population is(are) not known. Here we used a phage display approach and identified Siglec-9 as a candidate ligand on granulocytes. The binding between Siglec-9 and VAP-1 was confirmed by in vitro and ex vivo adhesion assays. The interaction sites between VAP-1 and Siglec-9 were identified by molecular modeling and confirmed by further binding assays with mutated proteins. Although the binding takes place in the enzymatic groove of VAP-1, it is only partially dependent on the enzymatic activity of VAP-1. In positron emission tomography, the 68Gallium-labeled peptide of Siglec-9 specifically detected VAP-1 in vasculature at sites of inflammation and cancer. Thus, the peptide binding to the enzymatic groove of VAP-1 can be used for imaging conditions, such as inflammation and cancer.

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von Gunten, Stephan, Alexander Schaub, Monique Vogel, Beda M. Stadler, Sylvia Miescher, and Hans-Uwe Simon. "Immunologic and functional evidence for anti–Siglec-9 autoantibodies in intravenous immunoglobulin preparations." Blood 108, no. 13 (December 15, 2006): 4255–59. http://dx.doi.org/10.1182/blood-2006-05-021568.

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Abstract Human intravenous immunoglobulin (IVIg) preparations are increasingly used for the treatment of autoimmune diseases. Earlier work demonstrated the presence of autoantibodies against Fas in IVIg, suggesting that IVIg might be able to induce caspase-dependent cell death in Fas-sensitive cells. In this study, we demonstrate that sialic acid–binding Ig-like lectin 9 (Siglec) represents a surface molecule on neutrophils that is activated by IVIg, resulting in caspase-dependent and caspase-independent forms of cell death. Neutrophil death was mediated by naturally occurring anti–Siglec-9 autoantibodies present in IVIg. Moreover, the efficacy of IVIg-mediated neutrophil killing was enhanced by the proinflammatory cytokines granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon-γ (IFN–γ), and this additional cell death required reactive oxygen species (ROSs) but not caspases. Anti– Siglec-9 autoantibody–depleted IVIg failed to induce this caspase-independent neutrophil death. These findings contribute to our understanding of how IVIg preparations exert their immunoregulatory effects under pathologic conditions and may provide a possible explanation for the neutropenia that is sometimes seen in association with IVIg therapy.

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Falahati, Rustom, Jessica Bright, Alejandro Dorenbaum, Christopher Bebbington, Nenad Tomasevic, Diane Lidke, Tracy I. George, and Jason Gotlib. "A Recombinant Antibody to Siglec-8 Shows Selective ADCC Activity Against Mast Cells from Systemic Mastocytosis Patients." Blood 126, no. 23 (December 3, 2015): 4092. http://dx.doi.org/10.1182/blood.v126.23.4092.4092.

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Abstract Background: Systemic mastocytosis (SM) is a rare myeloproliferative neoplasm characterized by the accumulation of neoplastic mast cells (MC) in one or more extracutaneous organs. In all forms of SM, anti-mediator drugs are used to control symptoms of MC degranulation. In advanced forms of SM, organ damage is common and patients (pts) exhibit reduced life expectancy. In these individuals, cytoreductive agents such as cladribine and interferon-alpha have been used off-label, and inhibitors of KIT D816V are under investigation. A significant unmet need exists for these patients. Siglec-8 is an inhibitory receptor of the CD33-related family of sialic acid-binding, Ig-like lectins (Siglecs) that is expressed selectively on the surface of mature MC, eosinophils, and basophils. Engagement of Siglec-8 with monoclonal antibodies has been previously shown to inhibit IgE-mediated MC degranulation and to induce apoptosis of cytokine-activated eosinophils. Thus this receptor is a potential target for antibody therapy of SM with or without associated eosinophilia. Anti-Siglec-8 antibodies do not directly affect MC viability but antibodies with effector function can induce antibody cell-mediated cytotoxicity (ADCC). Here we show that a recombinant anti-Siglec-8 IgG1 monoclonal antibody can elicit ADCC activity against MC derived from SM patients ex vivo. Methods: Bone marrow (BM) aspirates from SM patients were evaluated for Siglec-8 cell-surface expression on CD117+ FcεRI+ MC or CD25+ MC by flow cytometry. For ADCC assays, BM MC enriched using CD117-targeting magnetic beads or a Siglec-8 transfected Ramos cell line were used as target cells. Peripheral blood leukocytes (PBL) or NK cells purified from peripheral blood were used as effector cells at an effector:target ratio of 10:1. Recombinant anti-Siglec-8 antibody or an isotype control antibody was added at various concentrations and the percent viable CD117+ FcεRI+ MC remaining after 48 hours of culture was determined by flow cytometry. Results: Samples from 9 pts with SM were included in the analysis (ISM, n=1; SSM, n=1; SM-CMML, n=3; SM-MDS, n=1; SM-CEL, n=1; ASM, n=1; MCL, n=1). Eight pts were KIT D816V positive. At the time of sample collection, treatments included midostaurin (n=3); cladribine (n=1); corticosteroids (n=1); and 4 pts were not receiving any biologic or cytoreductive therapy. All BM samples showed detectable CD117+ MC. Robust and selective cell-surface expression of Siglec-8 was observed in all 6 cases evaluated and 100% of CD117+ FcεRI+ MC were Siglec-8 positive by FACS, including CD25+ MC. Levels of Siglec-8 were comparable to or higher than levels on mature MC isolated from normal skin. In this limited sample size, no difference in Siglec-8 expression was observed between patients receiving different therapies or no therapy. To evaluate the ADCC activity of recombinant anti-Siglec-8 antibody on MC, enriched BM MC were incubated with anti-Siglec-8 antibody or isotype-matched control antibody at 1 μg/ mL in the presence of purified NK effector cells. In two patients evaluated, significant anti-Siglec-8-mediated ADCC activity on MC was observed using non-autologous NK cells (69% reduction, 1 pt) or autologous NK cells (76% reduction, 1 pt) indicating that anti-Siglec-8 has the potential to reduce MC burden in these patients. ADCC activity has been reported to be defective in some cancer patients. To evaluate the ability of effector cells in SM patients to mediate ADCC, an assay was developed using a Siglec-8 transfected target cell line to screen blood samples for ADCC activity induced by anti-Siglec-8 antibody. Using PBL as effector cells, ADCC was observed in all samples tested (5/5). Titration of antibody was performed on 2 samples and potent ADCC activity was observed in both, with an EC50 for target depletion of 49 and 65 ng/mL of anti-Siglec-8 antibody, respectively. Conclusion: These data provide a strong rationale for evaluating the effect of an antibody to Siglec-8 with ADCC activity in patients with SM. Disclosures Falahati: Allakos, Inc.: Employment, Other: Options for Equity Owernship. Bright:Allakos, Inc.: Employment, Other: Options for Equity Owernship. Dorenbaum:Allakos, Inc.: Employment, Equity Ownership. Bebbington:Allakos, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Tomasevic:Allakos, Inc.: Employment, Equity Ownership. George:Allakos: Research Funding; Novartis: Consultancy. Gotlib:Allakos, Inc.: Consultancy.

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Wisnovsky, Simon, Leonhard Möckl, Stacy A. Malaker, Kayvon Pedram, Gaelen T. Hess, Nicholas M. Riley, Melissa A. Gray, et al. "Genome-wide CRISPR screens reveal a specific ligand for the glycan-binding immune checkpoint receptor Siglec-7." Proceedings of the National Academy of Sciences 118, no. 5 (January 25, 2021): e2015024118. http://dx.doi.org/10.1073/pnas.2015024118.

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Glyco-immune checkpoint receptors, molecules that inhibit immune cell activity following binding to glycosylated cell-surface antigens, are emerging as attractive targets for cancer immunotherapy. Defining biologically relevant ligands that bind and activate such receptors, however, has historically been a significant challenge. Here, we present a CRISPRi genomic screening strategy that allowed unbiased identification of the key genes required for cell-surface presentation of glycan ligands on leukemia cells that bind the glyco-immune checkpoint receptors Siglec-7 and Siglec-9. This approach revealed a selective interaction between Siglec-7 and the mucin-type glycoprotein CD43. Further work identified a specific N-terminal glycopeptide region of CD43 containing clusters of disialylated O-glycan tetrasaccharides that form specific Siglec-7 binding motifs. Knockout or blockade of CD43 in leukemia cells relieves Siglec-7-mediated inhibition of immune killing activity. This work identifies a potential target for immune checkpoint blockade therapy and represents a generalizable approach to dissection of glycan–receptor interactions in living cells.

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34

Blasius, Amanda L., Marina Cella, Jorge Maldonado, Toshiyuki Takai, and Marco Colonna. "Siglec-H is an IPC-specific receptor that modulates type I IFN secretion through DAP12." Blood 107, no. 6 (March 15, 2006): 2474–76. http://dx.doi.org/10.1182/blood-2005-09-3746.

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Abstract Natural interferon (IFN)-producing cells are the primary cell type responsible for production of type I IFN in response to viruses. Herein we report the identification of the first molecular marker of mouse natural interferon-producing cells (IPCs), a novel member of the sialic acid-binding immunoglobulin (Ig)-like lectin (Siglec) family termed Siglec-H. Siglec-H is expressed exclusively on IPCs and is unique among Siglec proteins in that it associates with the adaptor protein DAP12. Moreover, we show that DAP12 modulates the type I IFN response of IPCs to a Toll-like receptor 9 (TLR9) agonist. This observation explains our previous finding that stimulation of IPCs with 440c, a Siglec-H-specific antibody, reduces IPC secretion of type I IFN. Moreover, it supports a model in which engagement of DNAX-activation protein 12 (DAP12)-associated receptors with antibodies or low avidity endogenous ligands interferes with TLR-mediated cellular activation. (Blood. 2006;107:2474-2476)

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35

Shoji, Toru, Hiroshi Higuchi, Yoshinori Zaitsu, Ken-ichi Nishijima, and Shinji Iijima. "Enhanced lentiviral vector production in 293FT cells expressing Siglec-9." Cytotechnology 67, no. 4 (January 25, 2014): 593–600. http://dx.doi.org/10.1007/s10616-013-9679-7.

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36

Käkelä, Meeri, Pauliina Luoto, Tapio Viljanen, Helena Virtanen, Heidi Liljenbäck, Sirpa Jalkanen, Juhani Knuuti, Anne Roivainen, and Xiang-Guo Li. "Adventures in radiosynthesis of clinical grade [68Ga]Ga-DOTA-Siglec-9." RSC Advances 8, no. 15 (2018): 8051–56. http://dx.doi.org/10.1039/c7ra12423f.

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[⁶⁸Ga]Ga-DOTA-Siglec-9 is the first vascular adhesion protein-1 targeting radiopharmaceutical for positron emission tomography imaging of inflammation, and here we present its long-awaited clinical grade radiosynthesis.

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37

Angata, Takashi, and Ajit Varki. "Cloning, Characterization, and Phylogenetic Analysis of Siglec-9, a New Member of the CD33-related Group of Siglecs." Journal of Biological Chemistry 275, no. 29 (May 5, 2000): 22127–35. http://dx.doi.org/10.1074/jbc.m002775200.

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38

Kiser, Zachary Monroe, Greta L. Becker, Julia Nguyen, Anel Lizcano, John D. Belcher, Ajit P. Varki, and Gregory M. Vercellotti. "Decreased Erythrocyte Binding Capability for Neutrophil Siglec-9 Is a Source of Oxidative Stress in Sickle Cell Disease." Blood 132, Supplement 1 (November 29, 2018): 3650. http://dx.doi.org/10.1182/blood-2018-99-113579.

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Abstract Introduction Oxidative stress and inflammation promote hemolysis and vaso-occlusion in sickle cell disease (SCD). Erythrocytes can play a pro-oxidative and anti-oxidative role in disease-associated inflammation through iron-driven free radical production and endogenous anti-oxidants. In SCD, HbS accelerated auto-oxidation, iron de-compartmentalization, and inflammatory cell-derived oxidants drive this oxidative stress. CD33-related Sialic acid-binding immunoglobulin-type lectins (CD33rSiglecs) are cell surface proteins that recognize sialic acids in "Self-Associated Molecular Patterns" (SAMPs) and typically inhibit innate immune cell functions via cytosolic signaling. Recent studies have shown that Siglec-9 on human neutrophils in circulating blood interact with erythrocyte sialic acids (prominently glycophorin-A (GYPA) to suppress neutrophil reactivity, including reactive oxygen species (ROS) production. Modification of erythrocyte membrane sialic acids interferes with their ability to inhibit neutrophil activation and oxidative burst. As erythrocytes age and undergo cellular damage there is a loss of membrane bound sialoglycoproteins. Several studies have indicated that this reduction in the sialome is accelerated on the sickle erythrocyte. We hypothesize that altered sickle erythrocyte membrane sialic acid leads to decreased Siglec-9 binding capability, and that decreased binding of neutrophil Siglec-9 to sickle erythrocyte sialic acid enhances neutrophil activation and oxidative burst. Methods & Results Binding of recombinant Siglec-9-Fc protein to AA (n=9) and SS erythrocytes (n=7) was measured using flow cytometry. SS erythrocytes displayed significantly less Siglec-9-Fc binding 45% ± 11.9 (mean ± SEM) compared to AA erythrocytes 82% ± 5.4 (p=.03). Treatment of AA erythrocytes with neuraminidase to remove sialic acid decreased binding to 4% ± 7.9. Neutrophil ROS production was measured by flow cytometry using dihydrorhodamine 123 (DHR123). Neutrophils were purified from AA donors (n=5) and SS (n=11) or AA erythrocytes (n=5) were added to the neutrophils at a ratio of 50 erythrocytes to 1 neutrophil. Oxidative burst was stimulated using phorbol 12-myristate 13-acetate (PMA). AA erythrocytes decreased PMA-stimulated neutrophil ROS production by 84% ± 6.7. In contrast, SS erythrocytes decreased PMA-stimulated neutrophil ROS production by 53% ± 6.8 (p=0.03,). Recent studies have shown that neutrophil extracellular trap (NET) formation is pathogenic in SCD. We added AA and SS erythrocytes (50:1) to neutrophils stimulated with PMA and NET formation was assessed using Syto Orange, Syto Green and confocal microscopy. PMA-stimulated neutrophils incubated with AA erythrocytes showed minimal NET formation. In contrast, AA erythrocytes treated with neuraminidase to remove sialic acid had increased NET formation. PMA-stimulated neutrophils incubated with SS erythrocytes showed increased NET formation. Conclusions A constant disease state of oxidative stress and inflammation underlies SCD pathophysiology. These data demonstrate that SS erythrocytes with decreased membrane sialic acid are deficient in binding to neutrophil Siglec-9. The decreased binding of SS erythrocytes to neutrophil Siglec-9 diminishes the ability of SS erythrocytes to properly modulate neutrophil activation, which may contribute to the oxidative stress and increased state of basal inflammation inherent to SCD. The overall reduction in number of RBCs in SS may also be a factor? Figure. Figure. Disclosures Belcher: CSL Behring: Research Funding. Vercellotti:CSL Behring: Research Funding.

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39

Uchiyama, Satoshi, Josh Sun, Kyoko Fukahori, Nao Ando, Mengyou Wu, Flavio Schwarz, Shoib S. Siddiqui, Ajit Varki, Jamey D. Marth, and Victor Nizet. "Dual actions of group BStreptococcuscapsular sialic acid provide resistance to platelet-mediated antimicrobial killing." Proceedings of the National Academy of Sciences 116, no. 15 (March 25, 2019): 7465–70. http://dx.doi.org/10.1073/pnas.1815572116.

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Circulating platelets have important functions in thrombosis and in modulating immune and inflammatory responses. However, the role of platelets in innate immunity to bacterial infection is largely unexplored. While human platelets rapidly killStaphylococcus aureus, we found the neonatal pathogen group BStreptococcus(GBS) to be remarkably resistant to platelet killing. GBS possesses a capsule polysaccharide (CPS) with terminal α2,3-linked sialic acid (Sia) residues that mimic a common epitope present on the human cell surface glycocalyx. A GBS mutant deficient in CPS Sia was more efficiently killed by human platelets, thrombin-activated platelet releasate, and synthetic platelet-associated antimicrobial peptides. GBS Sia is known to bind inhibitory Sia-recognizing Ig superfamily lectins (Siglecs) to block neutrophil and macrophage activation. We show that human platelets also express high levels of inhibitory Siglec-9 on their surface, and that GBS can engage this receptor in a Sia-dependent manner to suppress platelet activation. In a mouse i.v. infection model, antibody-mediated platelet depletion increased susceptibility to platelet-sensitiveS. aureusbut did not alter susceptibility to platelet-resistant GBS. Elimination of murine inhibitory Siglec-E partially reversed platelet suppression in response to GBS infection. We conclude that GBS Sia has dual roles in counteracting platelet antimicrobial immunity: conferring intrinsic resistance to platelet-derived antimicrobial components and inhibiting platelet activation through engagement of inhibitory Siglecs. We report a bacterial virulence factor for evasion of platelet-mediated innate immunity.

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40

Nerreter, Thomas, Christoph Köchel, Daniel Jesper, Irina Eichelbrönner, Evelyn Putz, Hermann Einsele, and Ruth Seggewiss-Bernhardt. "Dasatinib enhances migration of monocyte-derived dendritic cells by reducing phosphorylation of inhibitory immune receptors Siglec-9 and Siglec-3." Experimental Hematology 42, no. 9 (September 2014): 773–82. http://dx.doi.org/10.1016/j.exphem.2014.05.010.

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41

Delaveris, Corleone S., Aaron J. Wilk, Nicholas M. Riley, Jessica C. Stark, Samuel S. Yang, Angela J. Rogers, Thanmayi Ranganath, Kari C. Nadeau, Catherine A. Blish, and Carolyn R. Bertozzi. "Synthetic Siglec-9 Agonists Inhibit Neutrophil Activation Associated with COVID-19." ACS Central Science 7, no. 4 (March 24, 2021): 650–57. http://dx.doi.org/10.1021/acscentsci.0c01669.

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42

Li, Xiang-Guo, Anu Autio, Helena Ahtinen, Kerttuli Helariutta, Heidi Liljenbäck, Sirpa Jalkanen, Anne Roivainen, and Anu J. Airaksinen. "Translating the concept of peptidelabeling with 5-deoxy-5-[18F]fluororibose into preclinical practice: 18F-labeling of Siglec-9 peptide for PET imaging of inflammation." Chemical Communications 49, no. 35 (2013): 3682–84. http://dx.doi.org/10.1039/c3cc40738a.

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43

Lizcano, Anel, Ismael Secundino, Simon Dohrmann, Ross Corriden, Lingquan Deng, Sandra Diaz, Victor Nizet, and Ajit P. Varki. "Erythrocyte Sialoglycoproteins Engage Siglec-9 to Maintain Neutrophil Quiescence in the Bloodstream." Blood 128, no. 22 (December 2, 2016): 1022. http://dx.doi.org/10.1182/blood.v128.22.1022.1022.

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Abstract Neutrophils remain functionally quiescent in the bloodstream of healthy humans. Characterized by a short lifespan (for which estimates vary widely), they exit the bloodstream to mediate various functions such as pathogen elimination or wound healing--or undergo spontaneous apoptosis and macrophage-mediated clearance in the absence of an inflammatory stimulus. Understanding of neutrophil quiescence, activation and lifespan is relevant to many clinical situations such as infection, sepsis, reperfusion injury, granulocyte transfusions, and other neutrophil-mediated inflammatory pathologies. It has long been known that neutrophils purified from blood tend to be short-lived and show signs of activation, but this technical challenge has been assumed to be a reflection of their natural biology in vivo. We found that when purified from whole blood, neutrophils indeed rapidly express activation markers (low L-selectin; high CD11b) and progress to apoptosis. However, using a novel method to label neutrophils in situ followed by flow cytometry, we found that these activation events occurred at a much slower rate in neutrophils that remained in whole blood. This finding led us to hypothesize that during separation of neutrophils from other blood components, one may be removing an inhibitor that normally maintains neutrophil quiescence in the bloodstream. Co-incubation studies showed that erythrocytes are the primary blood component that dampens neutrophil activation, including chemotaxis, generation of reactive oxygen species, and release of neutrophil extracellular traps. The duration of neutrophil viability was also lengthened upon re-incubation with erythrocytes. We found that this maintenance of functional quiescence is mediated largely by erythrocyte surface sialoglycoproteins (particularly glycophorin A, GPA), which engage neutrophil Siglec-9, a sialic acid-binding receptor that is known to dampen innate immune cell activation via cytosolic inhibitory motifs. Modification of erythrocyte sialic acid side chains using a newly developed gentle method eliminated Siglec-9 binding, and allowed neutrophil activation as measured by reactive oxygen species production. We next sought evidence that this interaction occurs in vivoby studying freshly collected whole blood. Smears made from fresh whole blood showed a high degree of Siglec-9 clustering on neutrophils, which was evident at points of contact with GPA on erythrocytes. This clustering was markedly reduced when smears were made from buffy coat preparations, which involves initial physical separation of neutrophils from erythrocytes during centrifugation. Taken together, this data indicates that erythrocyte sialic acids have an unexpected function as carriers of "self-associated molecular patterns" (SAMPs), regulating innate immunity and maintaining neutrophil quiescence in the bloodstream, apparently by tonic engagement of inhibitory Siglec-9. Notably, this SAMP effect blunts but does not completely inhibit bacterial killing by neutrophils in whole blood, and yet presumably helps to limit unwanted neutrophil inflammatory activation in the bloodstream. Our findings are relevant to many physiological, pathological and clinical situations involving neutrophil biology, and may be useful in reevaluation of prior studies of activation, function and reinfusion-based kinetics that were performed using neutrophils isolated away from whole blood. Disclosures No relevant conflicts of interest to declare.

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44

von Gunten, Stephan, Stephan M. Jakob, Barbara Geering, Jukka Takala, and Hans-Uwe Simon. "DIFFERENT PATTERNS OF SIGLEC-9-MEDIATED NEUTROPHIL DEATH RESPONSES IN SEPTIC SHOCK." Shock 32, no. 4 (October 2009): 386–92. http://dx.doi.org/10.1097/shk.0b013e3181a1bc98.

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45

Ando, Munetoshi, Toru Shoji, Wenjie Tu, Hiroshi Higuchi, Ken-ichi Nishijima, and Shinji Iijima. "Lectin-dependent localization of cell surface sialic acid-binding lectin Siglec-9." Cytotechnology 67, no. 4 (January 22, 2014): 601–8. http://dx.doi.org/10.1007/s10616-014-9691-6.

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46

Higuchi, Hiroshi, Toru Shoji, Yusuke Murase, Shinji Iijima, and Ken-ichi Nishijima. "Siglec-9 modulated IL-4 responses in the macrophage cell line RAW264." Bioscience, Biotechnology, and Biochemistry 80, no. 3 (November 5, 2015): 501–9. http://dx.doi.org/10.1080/09168451.2015.1104238.

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47

Schaub, A., S. von Gunten, M. Vogel, S. Wymann, M. Rüegsegger, B. M. Stadler, M. Spycher, H. U. Simon, and S. Miescher. "Dimeric IVIG contains natural anti-Siglec-9 autoantibodies and their anti-idiotypes." Allergy 66, no. 8 (March 9, 2011): 1030–37. http://dx.doi.org/10.1111/j.1398-9995.2011.02579.x.

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48

Ando, Munetoshi, Wenjie Tu, Ken-ichi Nishijima, and Shinji Iijima. "Siglec-9 enhances IL-10 production in macrophages via tyrosine-based motifs." Biochemical and Biophysical Research Communications 369, no. 3 (May 2008): 878–83. http://dx.doi.org/10.1016/j.bbrc.2008.02.111.

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49

Andes, F. T., S. Adam, M. Hahn, O. Aust, S. Frey, A. Grueneboom, L. Nitschke, G. Schett, and U. Steffen. "The human sialic acid-binding immunoglobulin-like lectin Siglec-9 and its murine homolog Siglec-E control osteoclast activity and bone resorption." Bone 143 (February 2021): 115665. http://dx.doi.org/10.1016/j.bone.2020.115665.

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Kitzig, Friederike, Águeda Martinez-Barriocanal, Miguel López-Botet, and Joan Sayós. "Cloning of two new splice variants of Siglec-10 and mapping of the interaction between Siglec-10 and SHP-1." Biochemical and Biophysical Research Communications 296, no. 2 (August 2002): 355–62. http://dx.doi.org/10.1016/s0006-291x(02)00885-9.

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