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

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

PROVIDER: PRJNA474508 | ENA |

REPOSITORIES: ENA

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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

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

Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration

Project description:We used mRNA-seq analysis to explore the transcriptional response induced in BV-2 cells by stable overexpression Siglec-F and related human Siglec receptors compared to loss-of-function 2xY->F mutant receptors.

2020-09-01 | GSE149153 | GEO

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

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

Project description: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.

2022-03-23 | GSE190700 | 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-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 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

The Inhibitory Receptor Siglec-8 Interacts with FcεRI and Globally Inhibits Intracellular Signaling in Primary Mast Cells Upon Activation

Project description:Immunomodulation of mast cell (MC) activity is warranted in allergic and inflammatory diseases where MCs have a central role in pathogenesis. Targeting Siglec-8, an inhibitory receptor on MCs and eosinophils, has shown promising activity in preclinical and clinical studies. While the intracellular pathways that regulate Siglec-8 activity in eosinophils have been well studied, the signaling mechanisms that lead to MC inhibition have not been fully elucidated. Here, we evaluate the intracellular signaling pathways of Siglec‐8‐mediated inhibition in primary MCs using an anti‐Siglec‐8 monoclonal antibody (mAb). Phospho‐proteomic profiling of FcεRI‐activated MCs revealed Siglec-8 mAb-treatment globally inhibited proximal and downstream kinases, leading to attenuated MC activation and degranulation. In fact, Siglec‐8 was found to directly interact with FcεRI signaling molecules. Siglec‐8 inhibition was dependent on both cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that interact with the SH2 containing protein phosphatase Shp-2 upon Siglec-8 phosphorylation. Taken together, these data support a model in which Siglec-8 regulates proximal FcεRI‐induced phosphorylation events through phosphatase recruitment and interaction with FcεRI, resulting in global inhibition of MCs upon Siglec-8 mAb engagement.

2022-01-21 | PXD030820 | Pride

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

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