Last update 01 Nov 2024

Siglec-9 x Siglec-7

Last update 01 Nov 2024

Basic Info

Related Targets

Siglec-9Siglec-7

Drugs associated with Siglec-9 x Siglec-7

HG-1230

Target

Siglec-7 x Siglec-9

Mechanism

Siglec-7 modulators [+1]

Active Org.-

Originator Org.

Human Genome Sciences, Inc.

Active Indication-

Inactive Indication

Immune System Diseases [+2]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with Siglec-9 x Siglec-7

100 Translational Medicine associated with Siglec-9 x Siglec-7

0 Patents (Medical) associated with Siglec-9 x Siglec-7

Literatures (Medical) associated with Siglec-9 x Siglec-7

01 Sep 2024·Clinical & Translational Immunology

Siglec‐7 and Siglec‐9 expression in primary triple negative and oestrogen receptor positive breast cancer and in vitro signalling

Article

Author: Granado, Daniel ; Adema, Gosse J ; Valk, Anne HC ; van Eck van der Sluijs, Jesper ; Lok, Jasper ; Cornelissen, Lenneke AM ; van Houtum, Eline JH ; van den Bogaard, Lune ; Span, Paul N ; Remkes, Naomi

AbstractObjectivesPD‐1/PD‐L1 immune checkpoint blockade can be an effective treatment for advanced breast cancer patients. However, patients with oestrogen receptor positive (ER+) tumors often display only low lymphocyte infiltration, while a large part of triple negative (TN) breast tumors does not generate an effective immunotherapy response. Therefore, new treatment strategies have to be developed. Here, we investigate Siglec‐7 and Siglec‐9 as novel ITIM‐bearing inhibitory immune checkpoint receptors similar to PD‐1, but expressed on a broader range of immune cells.MethodsWe assessed Siglec‐7 and Siglec‐9 (ligand) expression in TN and ER+ breast cancer tumors and their breast cancer cell line‐induced signalling.ResultsWe report that Siglec‐7 and Siglec‐9 are highly expressed in TN tumors, and to a low extent in ER+ tumors. Siglec‐7 was observed on myeloid cells, T cells, and NK cells and Siglec‐9 preferentially on myeloid cells. Expression of sialoglycans, including Siglec‐7 and Siglec‐9 ligands, was observed in both TN and ER+ breast cancer tissue sections. Expression levels of Siglec‐7 and Siglec‐9 ligands were higher on in vitro cultured TN cell lines than ER+ cell lines. Importantly, by applying chimeric Siglec‐7 reporter cells, we showed the induction of Siglec‐7 signalling by multiple TN cell lines, but only by one ER+ cell line. Moreover, Siglec‐7 signalling is directly related to Siglec‐7 ligand expression levels of breast cancer cell lines.ConclusionThese data imply that immunotherapy targeting Siglec receptors may be particularly interesting for TN breast cancer patients not responding to current treatment strategies with tumors displaying high immune cell infiltration.

28 Feb 2024·ACS Central Science

Dissecting the Ability of Siglecs To Antagonize Fcγ Receptors

Article

Author: McCord, Kelli A ; Macauley, Matthew S ; Poon, Wayne W ; Wu, Peng ; Wang, Chao ; Anhalt, Mirjam ; Gavin, Amanda L

Fcγ receptors (FcγRs) play key roles in the effector function of IgG, but their inappropriate activation plays a role in several disease etiologies. Therefore, it is critical to better understand how FcγRs are regulated. Numerous studies suggest that sialic acid-binding immunoglobulin-type lectins (Siglecs), a family of immunomodulatory receptors, modulate FcγR activity; however, it is unclear of the circumstances in which Siglecs can antagonize FcγRs and which Siglecs have this ability. Using liposomes displaying selective ligands to coengage FcγRs with a specific Siglec, we explore the ability of Siglec-3, Siglec-5, Siglec-7, and Siglec-9 to antagonize signaling downstream of FcγRs. We demonstrate that Siglec-3 and Siglec-9 can fully inhibit FcγR activation in U937 cells when coengaged with FcγRs. Cells expressing Siglec mutants reveal differential roles for the immunomodulatory tyrosine-based inhibitory motif (ITIM) and immunomodulatory tyrosine-based switch motif (ITSM) in this inhibition. Imaging flow cytometry enabled visualization of SHP-1 recruitment to Siglec-3 in an ITIM-dependent manner, while SHP-2 recruitment is more ITSM-dependent. Conversely, both cytosolic motifs of Siglec-9 contribute to SHP-1/2 recruitment. Siglec-7 poorly antagonizes FcγR activation for two reasons: masking by cis ligands and differences in its ITIM and ITSM. A chimera of the Siglec-3 extracellular domains and Siglec-5 cytosolic tail strongly inhibits FcγR when coengaged, providing evidence that Siglec-5 is more like Siglec-3 and Siglec-9 in its ability to antagonize FcγRs. Additionally, Siglec-3 and Siglec-9 inhibited FcγRs when coengaged by cells displaying ligands for both the Siglec and FcγRs. These results suggest a role for Siglecs in mediating FcγR inhibition in the context of an immunological synapse, which has important relevance to the effectiveness of immunotherapies.

01 Dec 2023·Immunologic Research

Integrated analyses delineate distinctive immunological pathways and diagnostic signatures for Behcet’s disease by leveraging gene microarray data

Article

Author: Li, Yongzhe ; Huang, Yuan ; Liu, Yongmei ; Yan, Songxin ; Cheng, Linlin ; Li, Haolong ; Zhan, Haoting ; Li, Xiaomeng

Behcet's disease (BD) is a chronic inflammatory vasculitis and clinically heterogeneous disorder caused by immunocyte aberrations. Comprehensive research on gene expression patterns in BD illuminating its aetiology is lacking. E-MTAB-2713 downloaded from ArrayExpress was analysed to screen differentially expressed genes (DEGs) using limma. Random forest (RF) and neural network (NN) classification models composed of gene signatures were established using the E-MTAB-2713 training set and subsequently verified using GSE17114. Single sample gene set enrichment analysis was used to assess immunocyte infiltration. After identifying DEGs in E-MTAB-2713, pathogen-triggered, lymphocyte-mediated and angiogenesis- and glycosylation-related inflammatory pathways were discovered to be predominant in BD episodes. Gene signatures from the RF and NN diagnostic models, together with genes enriched in angiogenesis and glycosylation pathways, well discriminated the clinical subtypes of BD manifesting as mucocutaneous, ocular and large vein thrombosis involvement in GSE17114. Moreover, a distinctive immunocyte profile revealed T, NK and dendritic cell activation in BD compared to the findings in healthy controls. Our findings suggested that EPHX1, PKP2, EIF4B and HORMAD1 expression in CD14+ monocytes and CSTF3 and TCEANC2 expression in CD16+ neutrophils could serve as combined gene signatures for BD phenotype differentiation. Pathway genes comprising ATP2B4, MYOF and NRP1 for angiogenesis and GXYLT1, ENG, CD69, GAA, SIGLEC7, SIGLEC9 and SIGLEC16 for glycosylation also might be applicable diagnostic markers for subtype identification.

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