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Induction of Local Immunosuppression in Allogenic Cell Transplantation by Cell-type-specific Expression of PD-L1 and CTLA4Ig

ABSTRACT: Induction of Local Immunosuppression in Allogenic Cell Transplantation by Cell-type-specific Expression of PD-L1 and CTLA4Ig

PROVIDER: PRJNA1014116 | ENA |

REPOSITORIES: ENA

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Induction of Local Immunosuppression in Allogenic Cell Transplantation by Cell-type-specific Expression of PD-L1 and CTLA4Ig

Project description:Immune rejection has long hindered allogenic cell transplantation therapy. Current genetic modification approaches, including direct targeting of major histocompatibility complex or constitutive expression of immune inhibitory molecules, exhibit drawbacks such as severe adverse effects or an elevated risk of tumorigenesis. To overcome these limitations, we propose an innovative approach aimed at inducing cell-type-specific immune tolerance in differentiated cells. By engineering human embryonic stem cells, we enable the exclusive production of immune inhibitory molecules, PD-L1/CTLA4Ig, within differentiated cells following lineage commitment. Leveraging this approach, we have successfully generated hepatocyte-like cells expressing PD-L1 and CTLA4Ig, which effectively induced local immunotolerance. This strategy was evaluated in a humanized mouse model designed to mimic human immune system. Our results demonstrate robust and selective induction of immunotolerance specific to hepatocytes, thereby improving graft survival without tumor formation. This precise immune tolerance strategy holds promise for advancing the development of stem cell-based therapeutics in regenerative medicine.

2023-12-20 | GSE242687 | GEO

Whole blood transcriptome analysis of Mycoplasma mycoides subsp, mycoides-infected cattle confirms immunosuppression but does not reflect local inflammation

Project description:In order to assess the use of whole blood transcriptome analysis to study cattle-Mmm interactions, we performed this study on 6 cattle, comparing the blood transcriptome before infection with the beginning of the clinical signs. Statistical analysis enabled Mmm-infected animals to be clearly distinguished from healthy ones. Functionnal analysis revealed that 680 genes were differentially expressed, confirming previous results as immunosuppression. Surprisingly, whoole blood transcriptome analysis didn't reflect inflammation, a highly characteristic local sign of these disease. This absence on inflammation signs results were confirmed by RT-qPCR. Whole blood gene expression was measured for each of 6 animals before infection and at the beginning of the clinical signs of CBPP. A paired sample statistical analysis was performed to identify diferentially expressed genes between healthy and infected status.

2015-06-20 | E-GEOD-70059 | biostudies-arrayexpress

A novel IFNα-induced long noncoding RNA, lncMX1-215, negatively regulates immunosuppression by interrupting H3K27 acetylation in head and neck squamous cell carcinoma

Project description:Interferon-alpha (IFNα) plays a ciritical role in immune regulation, especially in tumor microenvironment. Our previous study has demonstrated that IFNα promoted immunosuppression formation in head and neck squamous cell carcinoma. To explore the mechanism underlying IFNα-induced immunosuppression, long noncoding RNA (lncRNA) sequece was conduted. We identified a novel IFNα-induced upregulated lncRNA, lncMX1-215 in HNSCC. It was mainly located in cell nucleus. Ectopic expression of lncMX1-215 markedly inhibited IFNα-induced immunosuppression molecules, programmed cell death 1 ligand 1(PD-L1) and galectin-9 expression, and vice versa. Subsequently, histone deacetylase (HDAC) inhibitors promoted the expression of PD-L1 and galectin-9. There were binding sites of H3K27 acetylation on PD-L1 and galectin-9 promoters. Mechanically, we find that lncMX1-215 directly interacted with GCN5, a known H3K27 acetylase to interrupt its binding to H3K27 acetylation. Clinically, negative correlations between lncMX1-215 and PD-L1, galectin-9 were observed. Finally, overexpression of lncMX1-215 suppressed the proliferation and metastasis capacity in vitro and in vivo in HNSCC. Our results suggest that lncMX1-215 negatively regulates immunosuppression through interrupting GCN5/H3K27ac in HNSCC and provides novel insights into immune checkpoint blockade treatment.

2020-01-13 | GSE138147 | GEO

IFN -induced Immunosuppression in Lung Carcinoma is Mediated by an Environmental Chemical Receptor (AhR) through PD-L1 and IDO Control (cmt167 scRNA)

Project description:While immunotherapy has shown efficacy in non-small cell lung cancer (NSCLC) patients, many respond only partially or not at all. One limitation in improving outcomes is the lack of a complete understanding of factors regulating immune checkpoint targets. Here, we sought to address a possible link between an environmental chemical receptor implicated in NSCLC and immune regulation, the aryl hydrocarbon receptor (AhR), and a known but counterintuitive mediator of immunosuppression, IFN , in regulation of two immune checkpoints, PD-L1 and the IDO1, in lung adenocarcinoma (LUAD). To this end we used AhR, PD-L1, and IFN R gene-edited LUAD cell lines, a syngeneic LUAD mouse model, bulk- and single cell-RNA sequencing of LUADs and tumor-infiltrating leukocytes, and existing human transcriptomic databases. The data demonstrate that: 1) the AhR regulates both PD-L1 and IDO1 in murine and human LUAD cells, 2) AhR-driven IDO1 results in production of Kyn which likely mediates an AhR→IDO1→Kyn→AhR amplification loop, 3) the previously characterized induction by IFN of PD-L1 and IDO is mediated by the AhR, 4) transplantation of LUAD cells in which the AhR is deleted results in long-term tumor immunity in approximately half of the mice; slow growing tumors in the other half exhibit significantly higher densities of CD4+ and CD8+ T cells expressing immunocompetence markers, and 5) deletion of either IFN R1 or PD-L1 does not provide the same level of immune protection as AhR deletion. The data definitively link IFN - mediated immunosuppression to the AhR and support the targeting of the AhR in the context of LUAD.

2024-06-08 | GSE241979 | GEO

IFN -induced Immunosuppression in Lung Carcinoma is Mediated by an Environmental Chemical Receptor (AhR) through PD-L1 and IDO Control (cm167 bulk RNA)

2024-06-08 | GSE241978 | GEO

PD-1/CD80+ small extracellular vesicles from immunocytes induce cold tumours featuring with enhanced adaptive immunosuppression

Project description:Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as interaction pattern of immune checkpoint molecules carried on circulating small extracellular vesicles (sEV) might contribute to the low response rate. Here we demonstrate that PD-1 and CD80 carried on immunocyte-derived sEVs (I-sEV) induce an adaptive redistribution of PD-L1 in tumour cells. The resulting decreased cell membrane PD-L1 expression and increased sEV PD-L1 secretion into the circulation contribute to systemic immunosuppression. PD-1/CD80+ I-sEVs also induce downregulation of adhesion- and antigen presentation-related molecules on tumour cells and impaired immune cell infiltration, thereby converting tumours to an immunologically cold phenotype. Moreover, synchronous analysis of multiple checkpoint molecules, including PD-1, CD80 and PD-L1, on circulating sEVs distinguishes clinical responders from those patients who poorly respond to anti-PD-1 treatment. Altogether, our study shows that sEVs carry multiple inhibitory immune checkpoints proteins, which form a potentially targetable adaptive loop to suppress antitumour immunity.

2024-06-22 | PXD050744 | Pride

ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis [RNA-seq, anti-PD-L1 therapy]

Project description:ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis [RNA-seq, anti-PD-L1 therapy]

| PRJNA1174199 | ENA

Whole blood transcriptome analysis of Mycoplasma mycoides subsp, mycoides-infected cattle confirms immunosuppression but does not reflect local inflammation

2015-06-20 | GSE70059 | GEO

ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis

Project description:ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis

| PRJNA1170888 | ENA

Molecular Characterization of Acute Cellular Rejection Occurring during Intentional Immunosuppression Withdrawal in Liver Transplantation

Project description:Acute cellular rejection occurs frequently during the first few weeks following liver transplantation. During this period its molecular phenotype is confounded by pro-inflammatory events elicited by surgery, ischemia-reperfusion injury and early post-transplant complications. To unambiguously define the molecular profile associated with rejection we collected sequential biological specimens from liver transplant patients at least 3 years after transplantation who developed rejection while enrolled in trials of intentional immunosuppression withdrawal Transcriptomic RISET 2.0 chips were employed using portal blood vein from 37 liver trasplant patients.Two timepoints were selected: before immunosupressive weaning and rejection time point.

2016-06-01 | E-GEOD-70305 | biostudies-arrayexpress

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