Syndecan-1 inhibition promotes anti-tumor immune response and facilitates the efficacy of anti-PD1 checkpoint immunotherapy (kdSdc1 and mutant)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE254619 | GEO | 2024/09/18
REPOSITORIES: GEO
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Project description:To investigate the function of SDC1 in the regulation of anti-tumor immunity, we established B16 cell lines in which sdc1 or control RNA has been knocked down by shRNA. Then the cells were stimulated with or without IFNγ. We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 different groups, each group included three replicates.
2024-09-18 | GSE231355 | GEO
Project description:To illustrate the effects of SDC1 depletion on the tumor immune microenvironment, we performed single-cell RNA sequencing (scRNA-seq) analysis to interrogate phenotypic and functional alterations of immune cells in sdc1-knockdown vs. control tumors.
2024-09-18 | GSE231356 | GEO
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2024-09-18 | GSE231357 | GEO
Project description:To investigate whether the expression of ACSL4 may alter the anti-tumor effecet of T-cells, we conditionally knocked out the Acsl4 gene in mouse T-cells (Acsl4-cKO) as descried in Wang et al. Redox Biol 2022. To further demonstrate the importance of SM in ACSL4-mediated T-cell anti-tumor immunity, we conducted a complementary study by intra-tumoral injection of SM in subcutaneous MC38 tumors inoculated in Acsl4-cKO mice.
2024-05-23 | GSE233204 | GEO
Project description:Simultaneous blockade of immune checkpoint molecules and co-stimulation of the TNF receptor superfamily (TNFRSF) is predicted to improve overall survival in human cancer. TNFRSF co-stimulation depends upon coordinated antigen recognition through the T cell receptor followed by homotrimerization of the TNFRSF, and is most effective when these functions occur simultaneously. To address this mechanism, we developed a two-sided human fusion protein incorporating the extracellular domains (ECD) of PD-1 and OX40L, adjoined by a central Fc domain, termed PD1-Fc-OX40L. The PD-1 end of the fusion protein binds PD-L1 and PD-L2 with affinities of 2.08 and 1.76?nM, respectively, and the OX40L end binds OX40 with an affinity of 246 pM. High binding affinity on both sides of the construct translated to potent stimulation of OX40 signaling and PD1:PD-L1/L2 blockade, in multiple in vitro assays, including improved potency as compared to pembrolizumab, nivolumab, tavolixizumab and combinations of those antibodies. Furthermore, when activated human T cells were co-cultured with PD-L1 positive human tumor cells, PD1-Fc-OX40L was observed to concentrate to the immune synapse, which enhanced proliferation of T cells and production of IL-2, IFN? and TNF?, and led to efficient killing of tumor cells. The therapeutic activity of PD1-Fc-OX40L in established murine tumors was significantly superior to either PD1 blocking, OX40 agonist, or combination antibody therapy; and required CD4+ T cells for maximum response. Importantly, all agonist functions of PD1-Fc-OX40L are independent of Fc receptor cross-linking. Collectively, these data demonstrate a highly potent fusion protein that is part of a platform, capable of providing checkpoint blockade and TNFRSF costimulation in a single molecule, which uniquely localizes TNFRSF costimulation to checkpoint ligand positive tumor cells.
| S-EPMC6299665 | biostudies-literature
Project description:ObjectivesEpstein-Barr virus (EBV) infection is associated with a better response to anti-PD1 immunotherapy. We hypothesised that genetic alterations induced by EBV infection are responsible for the activation of key immune responses and hence are predictive of anti-PD1 efficacy.MethodsWith transcriptome data of gastric cancer (GC), we explored differentially expressed genes (DEGs) specific for EBV infection and performed coexpression network analysis using the DEGs to identify the consistent coexpression genes (CCGs) between EBV-positive and EBV-negative GC tissues. We selected the tag genes of the CCGs and validated them using RNA sequencing and immunohistochemistry. We established murine models and collected tissues from clinical patients to test the value of SLAMF8 in predicting anti-PD1 treatment. The location and expression of SLAMF8 were characterised by multiplex immunofluorescence and quantitative PCR. Moreover, exogenous overexpression and RNA-sequencing analysis were used to test the potential function of SLAMF8.ResultsWe identified 290 CCGs and validated the tag gene SLAMF8 in transcriptome data of gastrointestinal cancer (GI). We observed that the T-cell activation pathway was significantly enriched in high-expression SLAMF8 GI cancers. Higher SLAMF8 expression was positively associated with CD8 expression and a better response to anti-PD1 treatment. We further observed dynamically increased expression of SLAMF8 in murine models relatively sensitive to anti-PD1 treatment. SLAMF8 was mainly expressed on the surface of macrophages. Exogenous overexpression of SLAMF8 in macrophages resulted in enrichment of positive regulation of multiple immune-related pathways.ConclusionHigher SLAMF8 expression may predict better anti-PD1 immunotherapy efficacy in GI cancer.
| S-EPMC8546794 | biostudies-literature
Project description:Syndecans are cell surface proteoglycans that are involved in many physiopathological processes. To unveil the known signaling effects of shed Syndecan-1 (SDC1) in oral squamous cell carcinoma (OSCC), we overexpressed SDC1 ectodomain and its bioactive peptide and performed immunoaffinity purification followed by mass spectrometry analysis. Follistatin-related protein 1 (FSTL1) was identified with both overexpressed SDC1 forms, and their interaction was confirmed by the solid-phase binding, dot-blotting, confocal co-immunolocalization and selected reaction monitoring (SRM). We have also identified Activin A (ActA) in the SDC1 and pepSDC1 complexes. To further investigate the cross talk between these proteins, singled or doubled silenced SDC1 and FSTL1 OSCC cells were evaluated in an orthotopic mouse model. Tumor tissues showed an opposite epithelial-mesenchymal transition factors regulation, in which singled shSDC1 tissue showed decreased, while singled shFSTL1 and doubled shSDC1-FSTL1 tissues showed increased mRNA levels compared with the control. By Ki-67 immunoreactivity, shFSTL1 showed a higher proliferation than control, which can be explained by the increase in ActA and its receptors mRNA levels. These findings indicate that SDC1 and FSTL1 coordinate individually these two signaling events, acting more strongly on cell invasion and proliferation, respectively. To translate these effects on patient outcome based on their mRNA expression levels, we demonstrated that patients who have individual expression of SDC1 showed higher experience of metastasis than SDC1 and FSTL1 co-expression. This study underscores for the first time the close relationship between SDC1 and FSTL1, signaling, improving our understanding of the role of syndecan-1 in cancer progression.
2022-02-28 | PXD008377 | Pride
Project description:BackgroundPatients with advanced colorectal cancer (CRC) have a poor prognosis. Combinations of immunotherapies and anti-angiogenic agents are currently being evaluated in clinical trials. In this study, the multikinase inhibitor regorafenib (REG) was combined with an anti-programmed cell death protein 1 (aPD1) antibody in syngeneic murine microsatellite-stable (MSS) CT26 and hypermutated MC38 colon cancer models to gain mechanistic insights into potential drug synergism.MethodsGrowth and progression of orthotopic CT26 and subcutaneous MC38 colon cancers were studied under treatment with varying doses of REG and aPD1 alone or in combination. Sustained effects were studied after treatment discontinuation. Changes in the tumor microenvironment were assessed by dynamic contrast-enhanced MRI, and histological and molecular analyses.ResultsIn both models, REG and aPD1 combination therapy significantly improved anti-tumor activity compared with single agents. However, in the CT26 model, the additive benefit of aPD1 only became apparent after treatment cessation. The combination treatment efficiently prevented tumor regrowth and completely suppressed liver metastasis, whereas the anti-tumorigenic effects of REG alone were abrogated soon after drug discontinuation. During treatment, REG significantly reduced the infiltration of immunosuppressive macrophages and regulatory T (Treg) cells into the tumor microenvironment. aPD1 significantly enhanced intratumoral IFNγ levels. The drugs synergized to induce sustained M1 polarization and durable reduction of Treg cells, which can explain the sustained tumor suppression.ConclusionsThis study highlights the synergistic immunomodulatory effects of REG and aPD1 combination therapy in mediating a sustained inhibition of colon cancer regrowth, strongly warranting clinical evaluation in CRC, including MSS tumors.
| S-EPMC8436536 | biostudies-literature
Project description:Transcriptional profiling of tumor-infiltrating antigen-presenting myeloid subsets and CD8 T cells in mice bearing MC38-OVA tumors treated with or without radiotherapy, αSIRPα, and/or αPD-1 treatment
2022-04-19 | GSE197767 | GEO
Project description:PurposeAnti-programmed cell death protein 1 (PD1)±anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint inhibitors (ICIs) are standard therapeutic options for metastatic melanoma. We assessed whether biologic subtype according to primary tumor type or genomic subtype can function as predictive biomarkers for anti-PD1±anti-CTLA4 ICI in patients with advanced melanoma.MethodsWe performed a single-center retrospective cohort analysis of patients who received anti-PD1±anti-CTLA4 ICI for advanced melanoma between 2012 and 2019. Primary tumor type, BRAF and NRAS mutation status, and other covariates were abstracted from chart review. Log-rank tests and multivariable Cox regression models were used to assess differences in clinical progression-free (cPFS) and overall survival (OS).ResultsWe identified 230 patients who received 249 lines of anti-PD1±anti-CTLA4 ICI for unresectable or metastatic disease. Of these patients, 74% were cutaneous, 11% mucosal, 8% unknown primary and 7% acral. BRAF and NRAS mutations were identified in 35% and 28% of patients, respectively. In multivariable analyses of the entire cohort, acral or mucosal primary tumor type, >3 metastatic sites, elevated LDH were predictive of shorter cPFS and OS. Combination ICI therapy was associated with longer cPFS (HR 0.57, 95% CI 0.38 to 0.86, p=0.007) and OS (HR 0.42, 95% CI 0.28 to 0.65, p<0.001). Combination ICI was significantly associated with longer OS in unknown primary and mucosal melanoma. There was a non-significant trend toward longer OS with anti-PD1+anti-CTLA4 in cutaneous melanoma, but not in acral melanoma. In multivariable analyses, combination ICI was associated with longer OS in NRAS (HR 0.24, 95% CI 0.10 to 0.62, p=0.003, n=69) and BRAF V600E/K (HR 0.47, 95% CI 0.24 to 0.90, p=0.024, n=86) mutant melanoma but not BRAF/NRAS wild-type (n=94) melanoma.ConclusionsIn our cohort, primary melanoma tumor type and genomic subtype were independent predictive markers of cPFS and OS for patients with metastatic melanoma receiving anti-PD1 ICI. Primary tumor type and genomic subtype-including NRAS-should be further evaluated in prospective clinical trials to determine their value as predictive markers. Biologic subtypes may facilitate clinical decision-making when recommending combination ICI treatment (anti-PD1±anti-CTLA4) versus anti-PD1 alone for patients with metastatic melanoma.
| S-EPMC7831745 | biostudies-literature