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Siglec receptors modulate dendritic cell activation and antigen presentation to T cells in cancer

ABSTRACT: Sialoglycan - Siglec axis has been reported to modulate the functions of multiple immune cell types. We found that inhibitory molecules human Siglec-9 and mouse Siglec-E both expressed at high level in tumor-infiltrating dendritic cells(DCs). Therefore, we generated mouse DC cell line lacking the expression of Siglec-E, and used bulk RNA sequencying to analyse how Siglec-E affects DC functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE190700 | GEO | 2022/03/23

REPOSITORIES: GEO

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Self-associated molecular patterns mediate cancer immune evasion by engagement of Siglec receptors

Project description:Cancer immunotherapy targeting inhibitory receptors on T cells has changed the landscape of oncological practice, but most patients do not respond to current approaches. Thus, new targets on T cells for cancer immunotherapy are needed. CD33-related Siglecs are pattern recognition immune receptors binding to a broad range of sialoglycan ligands, which appear to function as self-associated molecular patterns (SAMPs) to dampen unwanted immune responses against self. Naïve T cells in humans have very low levels of inhibitory Siglec expression. Here, we show Siglec-9 in non-small cell lung cancer (NSCLC) are significantly upregulated on tumor-infiltrating T cells. These findings were confirmed in other tumor types including colorectal cancer, and ovarian cancer. Characterization of Siglec-9 expressing T cells showed a co-expression of inhibitory receptors including PD-1 and a distinct phenotype with increased cytokine production upon restimulation, compared to Siglec negative T cells. Functional analysis by reduction of sialoglycan-SAMPs on tumor cells in vitro and in vivo demonstrated an increased tumor cell killing and an inhibition of tumor growth. Overexpression of inhibitory Siglecs on T cells enhanced tumor growth in mice and exchange of inhibitory Siglecs on mouse T cells with an activating Siglec enhanced anti-cancer immunity. Increased T cell expression of Siglec-9 in NSCLC patients also correlated with survival, and analysis of Siglec-9 polymorphisms showed an association with the risk of developing lung and colorectal cancer. Our data identify the sialoglycan-SAMP/Siglec pathway as potential new target to improve T cell activation and cancer immunotherapy.

2018-12-26 | GSE115305 | GEO

Sialoglycans Modulate Siglec-5 – TLR4 Interactions in Osteoarthritis

Project description:Osteoarthritis (OA) is characterized by chronic, low-grade inflammation that contributes to cartilage degradation and joint pain. We previously identified Siglec-5/14 in synovial fluid of OA patients (OA SF), which prompted us to investigate its interaction with the sialylated proinflammatory receptor TLR4 in monocytes. Here, we reveal an inverse correlation between Siglec-5 and TLR4, suggesting Siglec-5 may suppress inflammation. To gain mechanistic insights, monocytes stimulated with OA SFs were compared to M-CSF, LPS, and sialidase, to assess patient-specific inflammatory pathways and phenotypes. Notably, OA SF that triggered elevated IL-6 production in monocytes exhibited phenotypes similar to those of LPS- or sialidase-treated cells, reinforcing the role of sialylation patterns influencing OA severity. To confirm direct interaction of Siglec-5 and TLR4, colocalization was analyzed, displaying a time- and sialoglycan- dependent interaction. These findings reveal a Siglec-5-TLR4 axis modulated by sialylation, highlighting a potential strategy for mitigating inflammation and preserve joint integrity in OA.

2025-10-27 | PXD069055 | Pride

Siglec Receptors Modulate Dendritic Cell Activation and Antigen Presentation to T Cells in Cancer.

Project description:Interactions between sialylated glycans and sialic acid-binding immunoglobulin-like lectin (Siglec) receptors have been recently described as potential new immune checkpoint that can be targeted to improve anticancer immunity. Myeloid cells have been reported to express a wide range of different Siglecs; however, their expression and functions on cancer-associated dendritic cells (DCs) were not fully characterized. We found that classical conventional DCs (cDCs) from cancer patient samples have a high expression of several inhibitory Siglecs including Siglec-7, Siglec-9, and Siglec-10. In subcutaneous murine tumor models, we also found an upregulation of the inhibitory Siglec-E receptor on cancer-associated cDCs. DC lines and bone marrow-derived DCs (BMDCs) with expression of these inhibitory Siglecs showed impaired maturation states on transcriptome and protein level. Furthermore, ablation of these inhibitory Siglecs from DCs enhanced their capability to prime antigen-specific T cells and induce proliferation. Our work provides a deeper understanding of the influence of inhibitory Siglecs on DCs and reveals a potential new target to improve cancer immunotherapy.

| S-EPMC8927547 | biostudies-literature

Siglec receptors modulate dendritic cell activation and antigen presentation to T cells in cancer

Project description:Siglec receptors modulate dendritic cell activation and antigen presentation to T cells in cancer

| PRJNA788124 | ENA

Proximity labeling of Siglec-1 counter-receptors on activated regulatory T cells using soluble Siglec-1-HRP multimers

Project description:Siglec-1 is a macrophage lectin-like receptor that mediates sialic acid-dependent cellular interactions. It was shown previously to promote inflammation in autoimmune disease through suppressing the expansion of regulatory T cells (Tregs). We have investigated the molecular basis for Siglec-1 binding to these cells using in vitro-induced Tregs. A proximity labelling and proteomics strategy were used to identify glycoproteins expressed by activated Tregs that may function as Siglec-1 counter-receptors.

2021-04-28 | PXD021693 | Pride

Proximity labeling of Siglec-1 counter-receptors on activated regulatory T cells using Siglec-1-HRP multimers on nano-beads

2021-04-28 | PXD021691 | Pride

Type-I interferon inducible genes 26 weeks after mCMV infection in Siglec-H wt and Siglec-H ko mice and their non infected controls

Project description:Type I interferons are critical anti-viral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The secretion of type I interferon of pDCs is modulated by Siglec-H, a DAP12 associated receptor on pDCs. We showed that Siglec-H deficient pDCs produce more of the type I interferon IFN-Î± in vitro and that Siglec-H ko mice produce more IFN-Î± after murine cytomegalovirus (mCMV) infection in vivo, leading to efficient clearance of the virus. Furthermore, ageing Siglec-H ko mice showed a mild form of systemic autoimmunity. In contrast, Siglec-H ko mice developed a severe form of systemic lupus-like autoimmune disease with strong kidney nephritis several weeks after a single mCMV infection. This induction of systemic autoimmune disease after virus infection in Siglec-H ko mice was accompanied by a type I interferon signature and fully dependent on type I interferon signaling. These results show that Siglec-H normally serves as modulator of type I interferon responses after infection with a persistent virus and thereby prevents induction of autoimmune disease. For microarray experiments gene expression profiles of total splenic cells from two wt and Siglec-H ko mice 26 weeks after infection with luciferase expressing murine Cytomegalovirus (5x105 pfu) or from two uninfected wt and Siglec-H ko control mice were analyzed

2016-03-16 | E-GEOD-79248 | biostudies-arrayexpress

Siglec-3 (CD33) and Siglec-8 ligands

Project description:Identification of human brain ligand for the microglial inhibitory receptors Siglec-3 (CD33) and Siglec-8

2022-03-07 | PXD032064 | JPOST Repository

Effect of soluble Siglec-14 on macrophage polarization

Project description:Influence of soluble Siglec-14 on macrophage poloarization was examined by analyzing the transcripts from human macrophages cultured in the presence or absence of recombinant soluble Siglec-14 protein

2018-10-29 | GSE121311 | GEO

Type-I interferon inducible genes 26 weeks after mCMV infection in Siglec-H wt and Siglec-H ko mice and their non infected controls

Project description:Type I interferons are critical anti-viral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The secretion of type I interferon of pDCs is modulated by Siglec-H, a DAP12 associated receptor on pDCs. We showed that Siglec-H deficient pDCs produce more of the type I interferon IFN-α in vitro and that Siglec-H ko mice produce more IFN-α after murine cytomegalovirus (mCMV) infection in vivo, leading to efficient clearance of the virus. Furthermore, ageing Siglec-H ko mice showed a mild form of systemic autoimmunity. In contrast, Siglec-H ko mice developed a severe form of systemic lupus-like autoimmune disease with strong kidney nephritis several weeks after a single mCMV infection. This induction of systemic autoimmune disease after virus infection in Siglec-H ko mice was accompanied by a type I interferon signature and fully dependent on type I interferon signaling. These results show that Siglec-H normally serves as modulator of type I interferon responses after infection with a persistent virus and thereby prevents induction of autoimmune disease.

2016-03-16 | GSE79248 | GEO

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