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Characteristics of a CCL21-gene modified dendritic cell vaccine utilized for a clinical trial in non-small cell lung cancer

ABSTRACT: Characteristics of a CCL21-gene modified dendritic cell vaccine utilized for a clinical trial in non-small cell lung cancer

PROVIDER: PRJNA1135255 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29818345.fastq.gz	Fastqsanger.gz
	SRR29818346.fastq.gz	Fastqsanger.gz
	SRR29818347.fastq.gz	Fastqsanger.gz
	SRR29818348.fastq.gz	Fastqsanger.gz
	SRR29818349.fastq.gz	Fastqsanger.gz

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Characteristics of a CCL21-gene modified dendritic cell vaccine utilized for a clinical trial in non-small cell lung cancer

Project description:Samples are from a phase I clinical trial of a vaccine consisting of monocyte-derived DCs (moDCs) modified to express the chemokine CCL21 given in combination with pembrolizumab, conducted in patients with advanced non-small cell lung cancer. Single cell RNA sequencing of pre- and post-transduced vaccines was performed to characterize the cellular composition of these vaccines and assess the trascriptional impact of the transduction process. The same vaccine production procedure was also applied to blood obtained from healthy donors to investigate the effects of donor source on DC vaccine phenotype.

2024-11-14 | GSE272174 | GEO

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CCL21 Expression in Beta Cells Induces Antigen-Expressing Stromal Cell Networks in the Pancreas and Prevents Autoimmune Diabetes in Mice

Project description:Tumors induce tolerance towards their antigens by producing the chemokine CCL21, leading to the formation of tertiary lymphoid organs (TLOs). Ins2-CCL21 transgenic, non-obese diabetic (NOD) mice express CCL21 in pancreatic β-cells and do not develop autoimmune diabetes. We investigated by which mechanisms CCL21 expression prevented diabetes. Islet infiltrates of 4 week-old Ins2-CCL21 mice were enriched in naïve CD4+ T cells and compartmentalized within networks of CD45- gp38+ CD31- fibroblastic reticular cell (FRC)-like stromal cells. Importantly, 12 week-old Ins2-CCL21 NOD islets contained FRC-like cells with enhanced expression of β-cell autoantigens and gene expression profiles consistent with regulatory, anti-inflammatory properties and increased contractility. Consistently, transgenic mice harbored fewer autoreactive T cells and higher proportion of Tregs in the islets. Using adoptive transfer and islet transplantation models, we demonstrate that the formation of TLOs in Ins2-CCL21 transgenic islets is critical for regulation of autoimmunity and while the effect is systemic, the induction may be mediated locally by lymphocyte trafficking through TLOs. Overall, our findings suggest that CCL21 promotes TLOs that differ from inflammatory TLOs associated with islets in T1D in that they resemble lymph nodes, contain FRC-like cells expressing β-cell autoantigens and are able to induce systemic and antigen-specific tolerance leading to diabetes prevention. These findings suggest that CCL21 may be exploited for novel immunoregulation approaches to treat autoimmune diabetes.

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CCL21/CCR7 axis in regulating glioblastoma stem cell-lymphatic endothelial cell interaction

Project description:CCL21/CCR7 axis in regulating glioblastoma stem cell-lymphatic endothelial cell interaction

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PTBP1 - Modified iCLIP

Project description:PTBP1 - Modified iCLIP

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GATA1-deficient dendritic cells display impaired CCL21-dependent migration towards lymph nodes due to reduced levels of polysialic acid

Project description:Dendritic cells (DCs) play a pivotal role in the regulation of the immune response. DC development and activation is finely orchestrated through transcriptional programs. GATA1 transcription factor is required for murine DC development and data suggests that it might be involved in the fine-tuning of the life span and function of activated DCs. We generated DC-specific Gata1 knockout mice (Gata1-KODC), which presented a 20% reduction of splenic DCs, partially explained by enhanced apoptosis. RNA-Seq analysis revealed a number of deregulated genes involved in cell survival, migration and function. DC migration towards peripheral lymph nodes was impaired in Gata1-KODC mice. Migration assays performed in vitro showed that this defect was selective for CCL21, but not CCL19. Interestingly, we show that Gata1-KODC DCs have reduced polysialic acid levels on their surface, which is a known determinant for the proper migration of DCs towards CCL21.

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Molecular mechanisms underlying the modulation of T-cell proliferation and cytotoxicity by immobilized CCL21 and ICAM1

Project description:A major challenge in adoptive cancer immunotherapy is the effective balance between the proliferation and cytotoxic capacity of the effector CD8+ T-cells. In this study we explored the molecular mechanisms whereby a “synthetic immune niche” (SIN), composed of immobilized CCL21 and ICAM1, modulates the interplay between these two cellular properties. Temporal phenotypic profiling of OVA-specific murine T-cells revealed major differences in the response to the SIN stimulation following antigen-specific and non-specific activation. Thus, SIN treatment enhanced both the expansion and cytotoxicity of cells activated by OVA-loaded DCs, at day 4, while, similar treatment of cells activated by anti CD3/CD28-conjugated beads dramatically enhanced the cells’ expansion, but unexpectedly blocked their cytotoxicity, which fully recovered only on day 7. Molecular profiling suggest that upregulation of cytotoxic gene signatures drive the SIN effect following DC activation, while down-regulation of exhaustion and pro-apoptotic genes optimize the proliferation-cytotoxicity balance in the beads-activated cells.

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