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

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

PROVIDER: PRJNA1069759 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27744900.fastq.gz	Fastqsanger.gz
	SRR27744901.fastq.gz	Fastqsanger.gz
	SRR27744902.fastq.gz	Fastqsanger.gz
	SRR27744903.fastq.gz	Fastqsanger.gz
	SRR27744904.fastq.gz	Fastqsanger.gz

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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.

2024-06-28 | GSE254335 | GEO

Development of potent antibody drug conjugates against ICAM1+ cancer cells in preclinical models of cholangiocarcinoma

Project description:We observed an interesting contradictory phenomenon that ICAM1-Dxd showed a very weak cytotoxicity on CCA cell lines in vitro, whereas it mediates more potent tumor attenuation than ICAM1-MMAE in vivo, suggesting the potency of ICAM1-Dxd may arise from its multifaceted biological activities instead of merely cytotoxicity. To elucidate its underlying biomechanism, we performed a transcriptomic RNA sequencing (RNA-seq) to profile the signaling pathways and key genes affected by ICAM1-Dxd treatment in PDX tumor tissues.

2023-09-20 | GSE233818 | GEO

Modulating the proliferative and cytotoxic properties of patient-derived TIL by a synthetic immune niche of immobilized CCL21 and ICAM1.

Project description:A major challenge in developing an effective adoptive cancer immunotherapy is the ex-vivo generation of tumor-reactive cells in sufficient numbers and with enhanced cytotoxic potential. It was recently demonstrated that culturing of activated murine CD8+ T-cells on a "Synthetic Immune Niche" (SIN), consisting of immobilized CCL21 and ICAM-1, enhances T-cell expansion, increases their cytotoxicity against cultured cancer cells and suppresses tumor growth in vivo. In the study reported here, we have tested the effect of the CCL21+ICAM1 SIN, on the expansion and cytotoxic phenotype of Tumor Infiltrating Lymphocytes (TIL) from melanoma patients, following activation with immobilized anti-CD3/CD28 stimulation, or commercial activation beads. The majority of TIL tested, displayed higher expansion when cultured on the coated SIN compared to cells incubated on uncoated substrate and a lower frequency of TIM-3+CD8+ cells after stimulation with anti-CD3/CD28 beads. Comparable enhancement of TIL proliferation was obtained by the CCL21+ICAM1 SIN, in a clinical setting that included a 14-day rapid expansion procedure (REP). Co-incubation of post-REP TIL with matching target cancerous cells demonstrated increased IFNγ secretion beyond baseline in most of the TIL cultures, as well as a significant increase in granzyme B levels following activation on SIN. The SIN did not significantly alter the relative frequency of CD8/CD4 populations, as well as the expression of CD28, CD25, several exhaustion markers and the differentiation status of the expanded cells. These results demonstrate the potential capacity of the CCL21+ICAM1 SIN to reinforce TIL-based immunotherapy for cancer patients.

| S-EPMC10020329 | biostudies-literature

RNA-seq of glioblastoma stem cells with CCL21 treatment

Project description:RNA-seq of glioblastoma stem cells with CCL21 treatment

2023-08-04 | GSE178337 | GEO

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.

2019-09-23 | GSE130979 | GEO

Differential gene expression of human natural killer cells following immobilized IgG1 stimulation

Project description:Analysis of human natural killer cells following stimulation with immobilized IgG1 for 4 and 24 hours. Results identified significantly differentially expressed genes in natural killer cells stimulated with immobilized IgG1 providing insight into how antibodies modulate the transcriptome in way that may contribute to cell activation and immune tolerance

2019-01-24 | GSE109573 | GEO

Mechanism of OGT-mediated FASN glycosylation regulating JNK/ICAM1 pathway in Liver cancer stem cell metastasis

Project description:We performed transcriptome sequencing analysis on LCSCs with different metastatic abilities. KEGG enrichment showed that genes upregulated during LCSC3 metastasis were related to cell membrane pathways. qPCR and flow cytometry confirmed that FASN expression was significantly upregulated during LCSCs metastasis. ICAM1 affects EMT, invadopodia formation, migration and invasion ability of LCSCs. ICAM1 plays a key role in the process of liver metastasis and the development of hepatocellular carcinoma in mice. FASN is also highly expressed during LCSC metastasis. Silencing FASN reduces the expression level of stemness genes, migration and invasion ability, and self-renewal ability of LCSCs. GSEA analysis indicated that transcriptome sequencing results after FASN knockdown were mainly enriched in the EMT process. FASN affects the expression of ICAM1 through the JNK/c-Jun axis in the MAPK pathway, and OGT is involved in the glycosylation process of ICAM1 regulating FASN, thereby affecting the migration ability of LCSCs.

2024-11-11 | GSE269783 | GEO

Mechanism of OGT-mediated FASN glycosylation regulating JNK/ICAM1 pathway in Liver cancer stem cell metastasis [Transwell]

2024-11-11 | GSE272352 | GEO

RNA-seq of glioblastoma stem cells with CCL21 treatment

Project description:RNA-seq of glioblastoma stem cells with CCL21 treatment

| PRJNA738513 | ENA

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.

2016-11-08 | GSE69969 | GEO

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