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The lectin Siglec-G functions as an inhibitory receptor in CD8+ T cell and can be targeted to enhance therapeutic antitumor immunity.

ABSTRACT: CD8+ T cells play a critical role in cancer immune-surveillance and pathogens elimination. However, the effector function of CD8+ T cells may be severely influenced due to inhibitory receptors. Here we identify Siglec-G as a coinhibitory receptor that plays a critical role in limiting the function of CD8+ T cells. Siglec-G is highly expressed on both human and murine tumor-inﬁltrating T cells, and SiglecG+ T cells enriched in the exhausted T cell subset. CD24-Siglec-G-SHP2 axis negatively regulates PI3K-AKT signaling and impairs metabolic reprogramming in CD8+ T cells and thereby dampens their activation, expansion and cytotoxicity. Genetic ablation of Siglec-G can enhance the efficacy of adoptively transferred T cells and CAR T cells to repress the growth of solid tumors. These results deﬁne a key role for Siglec-G in inhibiting CD8+ T cell-dependent responses, which strongly suggested its therapeutic effect in adoptive T cell therapy and tumor immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE255336 | GEO | 2024/12/18

REPOSITORIES: GEO

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Siglec-G suppresses CD8+ T cells responses through metabolic rewiring and can be targeted to enhance tumor immunotherapy

Project description:CD8+ T cells play a critical role in cancer immune-surveillance and pathogens elimination. However, their effector function can be severely impaired due to inhibitory receptors such as PD-1 and Tim-3. Here we identify Siglec-G as a novel coinhibitory receptor that limits CD8+ T cell function. Siglec-G is highly expressed on tumor-inﬁltrating T cells and is enriched in the exhausted T cell subset. Ablation of Siglec-G enhances the efficacy of adoptively transferred T cells and CAR T cells to repress the growth of solid tumors. Mechanistically, sialic acids on tumor cells trigger Siglec-G-SHP2 axis in CD8+ T cells, and impairs metabolic reprogramming from OXPHOS to glycolysis, which dampens CTL activation, expansion and cytotoxicity. These findings deﬁne a critical role for Siglec-G in inhibiting CD8+ T cell responses, which strongly suggests its therapeutic effect in adoptive T cell therapy and tumor immunotherapy.

2024-12-18 | GSE272544 | 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

Tumor-derived kynurenine induces Siglec-15 expression and promotes CD8+T cell exhaustion in oral squamous cell carcinoma

Project description:Metabolic deregulation and immune escape are pivotal hallmarks of cancer; however, the profile of metabolic reprogramming in oral squamous cell carcinoma (OSCC) and how it drives immune escape remain unclear. We identified significant metabolic disorders in OSCC. Amino acid metabolism, especially tryptophan/kynurenine metabolism, was altered. Here, we found that kynurenine promotes migration, invasion, and proliferation in vitro and in vivo. In addition, most immune checkpoints were upregulated in patients with high kynurenine levels. We then identified that kynurenine can promote Siglec-15 expression via AhR activation. Furthermore, tumor-derived kynurenine can directly exhaust CD8+ T cells, whereas blocking of kynurenine transporters reversed this effect. Moreover, we found that ectopic expression of Siglec-15 can promote immune escape in tumor microenvironment (TME) by suppressing T cell infiltration and inducing CD8+ T cell exhaustion in vivo, while targeting AhR reduces kynurenine-mediated immune escape. Finally, we design NH2-MSNs nanoparticles to deliver Siglec-15 small interfering RNA, which successfully remodels the TME and enhances anti-PD-1 efficacy in tumor-bearing immunocompetent mice. Clinically, Siglec-15 expression is correlated with AhR expression and high infiltration of exhausted CD8+ T cells. These findings reveal that the Kyn/AhR/Siglec-15 signaling pathway is a novel immunometabolism mechanism in OSCC, thus opening a new therapeutic avenue for metabolic immunotherapy.

2024-07-03 | GSE222673 | GEO

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.

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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.

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RNA sequencing to determine gene expression changes in Siglec-15 knockdown oteosarcoma cells

Project description:In our study, we found that Siglec-15 was critical to osteosarcoma characteristics. To identify the downstream target genes of Siglec-15 in osteosarcoma, we conducted the RNA-seq analysis of Siglec-15 knockdown in osteosarcoma cell line 143B cells.

2021-05-25 | GSE175414 | GEO

Identification of proteins that interact with Siglec-6

Project description:Siglec-6 is a glycoprotein overexpressed on chronic lymphocytic leukemia (CLL) cell. We have shown that Siglec-6 promotes migration and adhesion of CLL cells towards CLL bone marrow stromal cells. To elucidate the mechanistic pathway involved in Siglec-6 dependent migration, we performed mass spectrometry proteomics analysis on MEC1-002 CLL cell line pulled down with a Siglec-6 targeted antibody, which revealed that Siglec-6 interacts with DOCK8, a guanine nucleotide exchange factor. Interaction of Siglec-6 with its ligand promotes DOCK8 dependent Cdc42 activation, WASP protein recruitment and F-actin polymerization. Therapeutically, Siglec-6 leukemic cells can be eliminated with a Siglec-6 targeted bispecific antibody in vitro and in vivo.

2024-05-08 | PXD039892 | 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

The inhibitory receptor Siglec-G controls the severity of chronic lymphocytic leukemia

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2023-05-03 | GSE227678 | GEO

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

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