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Статті в журналах з теми "Siglec- 9/siglec-E"
1
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.
Повний текст джерелаАнотація:
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.
2
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.
Повний текст джерелаАнотація:
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.
3
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.
Повний текст джерелаАнотація:
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.
4
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.
Повний текст джерелаАнотація:
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.
5
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.
Повний текст джерелаАнотація:
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.
6
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.
Повний текст джерелаАнотація:
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.
7
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.
Повний текст джерелаАнотація:
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.
8
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.
Повний текст джерела
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Egan, Hannah, Oliver Treacy, Kevin Lynch, Niamh Leonard, Amir Nader, Margaret Sheehan, Sean Hynes, et al. "865 Sugar high: Does the sialic acid profile of cancer-associated fibroblasts induce a more tumour-permissive microenvironment?" Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A918. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0865.
Повний текст джерелаАнотація:
BackgroundImmunosuppressive tumour microenvironments (TME) inhibit the effectiveness of cancer immunotherapies. Sialic acids, which exist as terminal sugars of glyco-conjugates, are highly expressed on cancer cells and are involved in various pathological processes including increased immune evasion, tumour invasiveness and tumour cell metastasis.1 Siglecs (Sialic acid-binding immunoglobulin-type lectins) are expressed on immune cell surfaces and bind sialic acid. Siglec binding to hypersialylated tumour glycans blocks immune cell activation to promote immunosuppression.1 2Intestinal stromal cells (iSCs), precursors to cancer-associated fibroblasts (CAFs), are a key component of the TME and play a vital role in tumour progression by enhancing a tumour-promoting microenvironment. The aim of this study was therefore to investigate if iSC/CAF sialylation contributes to enhanced immunosuppression in the TME.Methods iSCs were isolated from colorectal cancer patient biopsies and cultured ex vivo. Informed consent was obtained from all patients prior to sampling. Tumour-derived iSCs were termed CAFs while control iSCs, isolated from tumour-adjacent non-cancerous tissue, were termed normal-associated fibroblasts (NAFs). NAFs/CAFs were then co-cultured with healthy allogeneic PBMCs and their immunosuppressive properties were assessed by flow cytometry.ResultsCAFs significantly supressed the proliferation of CD8+ and CD4+ T-cells and induced a more exhausted T-cell phenotype as evidenced by increased expression of the exhaustion markers TIM-3, LAG-3 and PD-1 when compared to co-culture with control NAFs, thereby demonstrating their potent immunosuppressive properties. Strikingly, CAFs also induced significantly higher expression of both Siglec-7 and Siglec-9 receptors on CD8+ T-cells specifically.To elucidate the role of sialylation on CAF-mediated immunosuppression, NAFs/CAFs were treated with the sialyltransferase inhibitor (SI) P-3FAX-Neu5Ac prior to co-culture. Reduction of sialic acid expression on NAFs/CAFs was confirmed by flow cytometry and the SI-treated NAFs/CAFs were then co-cultured with allogeneic T-cells to assess the functional consequences of reduced NAF/CAF sialylation. SI-treated CAFs induced significantly less CD4+TIM-3+ and both CD4+LAG-3+ and CD8+LAG-3+ T-cells compared to their untreated counterparts. Interestingly, SI-treated CAFs also induced significantly less Siglec-7 and -9 receptor-expressing CD8+ T-cells.ConclusionsThese results demonstrate that non-haematopoietic stromal cells in the tumour-microenvironment can suppress activated T-cells and that this immunosuppressive effect can be significantly reversed through the modulation of sialylation on the stromal cell surface. These results support the hypothesis that stromal cell sialylation plays a role in their immunosuppressive properties. Understanding how sialylation of stromal cells is regulated and functions to enhance immunosuppression in the TME could uncover novel immune checkpoints to reactivate anti-tumour immunity, allowing for tumour cell clearance.Ethics ApprovalThis study was approved by Galway University Hospitals’ Clinical Research Ethics Committee, approval number C.A 2074.ConsentN/AReferencesWang L, Liu Y, Wu L, Sun XL. Sialyltransferase inhibition and recent advances. Biochim Biophys Acta 2016 Jan; 1864(1):143-53.Munkley J, Scott E. Targeting aberrant sialylation to treat cancer. Medicines (Basel) 2019 Oct 13;6(4):102.
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Yoon, Soyon, Seokcheon Song, Jae Woo Shin, Sini Kang, Hye Young Kim, and Hyun Ju You. "Protective Effects of Korean Herbal Remedy against Airway Inflammation in an Allergic Asthma by Suppressing Eosinophil Recruitment and Infiltration in Lung." Antioxidants 10, no. 1 (December 23, 2020): 6. http://dx.doi.org/10.3390/antiox10010006.
Повний текст джерелаАнотація:
The increasing prevalence of allergic asthma has become the world’s major health issue. Current treatments for allergic asthma focus on treating symptoms, while permanent cures still remain undiscovered. In this study, we investigated the effect of Korean traditional herbal remedy, Pyunkang-tang (PGT)—composed of six plants—on asthma alleviation in a mouse model. The PGT mixture was orally gavaged to mice (PM group, 20 mg/mouse/day) from 7 days before sensitization with ovalbumin (OVA) (day −7). On day 0 and day 14, mice from OVA-control (n = 9) and PM group (n = 8) were sensitized with OVA and alum through intraperitoneal injection. On days 18~20, OVA was challenged to mice through nasal injection and sacrificed next day. Cell profile in lung tissue was analyzed by flow cytometry and RT-qPCR analysis, and the number of eosinophils and expression of siglec-F were significantly reduced in the PM group. Lung tissue was examined with hematoxylin and eosin (H&E) and Alcian blue/periodic acid–Schiff (AB-PAS) staining. Noticeably reduced eosinophil infiltration around bronchioles was displayed in the PM group compared to the OVA-control group. Furthermore, PGT-treated mice showed a significant reduction in IL-13 and a mild reduction in IL-5 in lungs. A decreasing tendency of IL-5/13 (+) CD4+ T cells and IL-13(+) innate lymphoid cells (ILCs) and a significant reduction in IL5(+) ILCs were also observed. When treating PGT on murine lung epithelial cells stimulated by papain, there was a significant reduction in IL-33 mRNA expression levels. Taken together, oral delivery of PGT successfully alleviated asthmatic responses provoked by OVA in a mouse model and could lead to novel therapies for allergic asthma.
Дисертації з теми "Siglec- 9/siglec-E"
1
Kuol, Nyanbol. "Interaction Between Immunosuppressive and Cholinergic Markers in Colorectal Cancer." Thesis, 2020. https://vuir.vu.edu.au/42036/.
Повний текст джерелаАнотація:
Colorectal cancer (CRC) is amongst the leading diagnosed cancers worldwide. Despite the increasing interest to understand, the roles that the nervous and immune systems play in influencing the tumour microenvironment to promote cancer development and progression, more studies are required to understand the mechanism. Cancer cells can influence their microenvironment and bi-directionally communicate with other systems such as the immune and nervous systems. The immune system plays a key role in the eradication of cancer cells. Studies have shown that multiple mechanisms are responsible for the suppression of the immune system in cancer, one of which being the expression of immune checkpoints inhibitors such as programmed death 1 (PD-1), PD-L1, programmed death ligand 1 and 2 (PD-L1, PD- L2), sialic acid-binding lectins 9 (siglec-9) and IDO (indoleamine-2,3-dioxygenase). These molecules function by inhibiting anti-tumour effects of T cell-mediated immune responses. In addition to these molecules, studies have shown that several cancers can release acetylcholine (ACh) and express cholinergic receptors (muscarinic receptor 3 (M3R) and alpha 7 nicotinic receptor (a7nAChR)), overexpress choline acetyltransferase (ChAT), a precursor enzyme required for ACh synthesis and VAChT, essential for transporting of ACh, and excitatory receptor. Currently, there are no data available in determining the interaction between the expression of immunosuppressive and cholinergic markers in cancer, thus, this thesis aims to determine the interaction between the expression of immunosuppressive and cholinergic markers in CRC.