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T cell dependent bispecific antibodies (TDBs) promote T cell redistribution through organ-specific alteration of vascular endothelial cell (scRNAseq)

ABSTRACT: TDBs (T cell dependent bispecific antibodies) have an agonistic anti-CD3 arm paired with a tumor-targeting arm that recognizes tumor-restricted/enriched cell-surface proteins. Preclinical and clinical studies demonstrated that TDBs can induce systemic changes in addition to their expected action in tumors, including transient loss of circulating leukocytes (margination), systemic cytokine release, and accumulation of lymphocytes in normal tissues. These reactions can lead to undesirable symptoms including cytokine release syndrome and liver enzyme elevation. Here, we report for the first-time an in-depth characterization of acute responses in tumor and liver upon TDB treatment. We observed rapid and substantial accumulation of lymphocytes around large blood vessels in normal organs such as the liver, accompanied by elevated vascular endothelial cell (EC) activation markers. We hypothesized that organ-specific EC phenotypes may account for the differential T cell accumulation in normal tissues versus tumors. Despite ongoing efforts to better characterize specific properties of ECs, the underlying transcriptional changes of specific endothelial cell subtypes influencing the T cell trafficking and accumulation in non-target-expressing organs (like here liver) upon TDB treatment are unknown. The purpose of the study is to investigate the effect of anti-HER2/CD3 TDB treatment on the endothelial cells in the liver and characterize possible transcriptional changes occurring.

ORGANISM(S): Mus musculus

PROVIDER: GSE198868 | GEO | 2022/12/09

REPOSITORIES: GEO

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T cell dependent bispecific antibodies (TDBs) promote T cell redistribution through organ-specific alteration of vascular endothelial cell (bulk RNAseq)

Project description:TDBs (T cell dependent bispecific antibodies) have an agonistic anti-CD3 arm paired with a tumor-targeting arm that recognizes tumor-restricted/enriched cell-surface proteins. Preclinical and clinical studies demonstrated that TDBs can induce systemic changes in addition to their expected action in tumors, including transient loss of circulating leukocytes (margination), systemic cytokine release, and accumulation of lymphocytes in normal tissues. These reactions can lead to undesirable symptoms including cytokine release syndrome and liver enzyme elevation. Here, we report for the first-time an in-depth characterization of acute responses in tumor and liver upon TDB treatment. We observed rapid and substantial accumulation of lymphocytes around large blood vessels in normal organs such as the liver, accompanied by elevated vascular endothelial cell (EC) activation markers. We hypothesized that organ-specific EC phenotypes may account for the differential T cell accumulation in normal tissues versus tumors. Despite ongoing efforts to better characterize specific properties of ECs, the underlying transcriptional changes of specific endothelial cell subtypes influencing the T cell trafficking and accumulation in non-target-expressing organs (like here liver) upon TDB treatment are unknown. The purpose of the study is to investigate the effect of anti-HER2/CD3 TDB treatment on the endothelial cells in the liver and characterize possible transcriptional changes occurring.

2022-12-09 | GSE198867 | GEO

Acute venous hypertension induces local release of inflammatory cytokines and endothelial activation in humans

Project description:Background: Venous hypertension is often present in advanced and in acute decompensated heart failure (HF). However, it is unclear whether high intravenous pressure can cause alterations in homeostasis by promoting inflammation and endothelial cell (EC) activation. We used an experimental model of acute, local venous hypertension to study the changes in circulating inflammatory mediators and EC phenotype that occur in response to biomechanical stress. Methods and Results: Twenty-four healthy subjects (14 men, age 35±2 years) were studied. Venous arm pressure was increased to ~30 mmHg above baseline level by inflating a tourniquet cuff around the dominant arm (test arm). Blood and endothelial cells (ECs) were sampled from test and control arm (lacking an inflated cuff) before and after 75 minutes of venous hypertension, using angiocatheters and endovascular wires. Magnetic beads coated with EC specific antibodies were used for EC separation; amplified mRNA was analyzed by Affymetrix HG-U133 2.0 Microarray. Plasma endothelin-1 (ET-1), interleukin-6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1) and chemokine (C-X-C motif) ligand 2 (CXCL2) were significantly increased in the congested arm. 5,332 probe sets were differentially expressed in venous ECs before vs. after testing. Among the 143 probe sets that exhibited a significant absolute fold change >2, we identified several inflammatory mediators including ET-1, VCAM-1, and CXCL2. Conclusions: Acute experimental venous hypertension is sufficient to cause local increase in circulating inflammatory mediators and to activate venous ECs in healthy human subjects. Additional work is needed to determine the effect of venous hypertension in patients with established HF. 24 samples were analyzed from 12 patients. Each patient contributed 2 samples (1 prior to intervention and 1 after intervention). The pre-intervention sample serves as the control.

2013-12-04 | E-GEOD-38783 | biostudies-arrayexpress

Acute venous hypertension induces local release of inflammatory cytokines and endothelial activation in humans

2013-12-04 | GSE38783 | GEO

fecf2d5b-af47-4610-a1a9-329acff72227 - samples

Project description:Single-cell RNA-seq libraries were generated from human PBMCs that were incubated with anti-HER2/CD3 TDB in the presence of KPL-4 cells. This dataset is linked with the following ArrayExpress Experiment: E-MTAB-8212 - The effect of anti-HER2/CD3 TDB on transcription in human PBMCs (single-cell)

| EGAD00001005188 | EGA

The effect of anti-HER2/CD3 TDB on transcription in human PBMCs (single-cell)

Project description:Single-cell RNA-seq libraries were generated from human PBMCs that were incubated with anti-HER2/CD3 TDB in the presence of KPL-4 cells. This dataset only contains the metadata and processed data. Raw data can be accessed via the EGA accession EGAS00001003734

2019-09-06 | E-MTAB-8212 | biostudies-arrayexpress

Single-cell RNA sequencing reveals transcriptome alterations of liver sinusoidal endothelial cells in different zonal microenvironments of cirrhotic livers

Project description:Dysfunction of liver endothelial cells (ECs), especially sinusoid endothelial cells (LSECs), play a key role in progression of liver fibrosis/cirrhosis. Here, we reported a map which reveals heterogeneity and spatial distribution of liver ECs in normal versus cirrhotic mouse liver and determined liver zonal specific transcriptomic changes of LSECs associated with liver cirrhosis using single-cell RNA sequencing technology. We identified 6 clusters of liver EC populations including 3 clusters of LSECs, 2 clusters of vascular ECs (arterial and central venous ECs) and 1 cluster of lymphatic ECs. Particularly, we mapped the 3 clusters of LSECs in Zone1-3. We found that liver EC identities are conserved even in liver cirrhosis and that Zone3 LSECs are most susceptible to damages associated with liver cirrhosis with increased capillarization and decreased abilities to regulate endocytosis and vascular tone. Altogether, this study deepens our knowledge for the pathophysiology of cirrhosis at a spatial and cell-specific level, which are indispensable for the development of novel therapeutic strategies to target liver ECs.

2021-02-05 | GSE147581 | GEO

single-cell transcriptional profiling of human cholestatic livers

Project description:Cholestatic liver diseases are characterized by excessive accumulation of bile acids in the liver. The involvement of local tissue microenvironment in cholestatic diseases remains poorly understood. Here, we performed a comprehensive analysis of liver single-cell transcriptomic study of human cholestatic liver diseases. Our study involved 9 liver samples obtained from 7 patients diagnosed with hepatatrophia resulting from cholestasis. By utilizing single-cell data, we gained valuable insights into the specific functions of endothelial cells (EC) in response to chenodeoxycholic acid during cholestasis. The findings from our study hold the potential to lay the groundwork for personalized therapeutic approaches in the future, tailored to the individual needs of patients.

2023-07-22 | GSE237622 | GEO

Gata4 and LMO3 balance angiocrine signaling and autocrine inflammatory activation by BMP2 in liver sinusoidal endothelial cells [HUVEC]

Project description:Liver sinusoidal endothelial cells (LSEC) represent a unique, organ-specific type of discontinuous endothelial cells. LSEC instruct the hepatic vascular niche by paracrine-acting angiocrine factors. Recently, we have shown that LSEC-specific transcriptional regulator GATA4 induces expression of BMP2 in cultured endothelial cells (EC) in vitro. Furthermore, angiocrine Bmp2 signaling in the liver in vivo was demonstrated to control iron homeostasis. Here, we investigated GATA4-dependent autocrine BMP2 signaling in endothelial cells by gene expression profiling. GATA4 induced a large cluster of inflammatory endothelial response genes in cultured EC, which is similar to previously identified virus-induced and interferon-associated responses. Treating the cells with the BMP2 inhibitor Noggin counter-regulated the GATA4-dependent inflammatory phenotype of EC, indicating that BMP2 is indeed the major driver. In contrast to continuous EC, LSEC were less prone to activation by BMP2. Notably, GATA4-dependent induction of the inflammatory EC response gene cluster was attenuated by over-expression of the LSEC-specific transcriptional modifier LMO3 while hepatocyte activation was fully preserved, indicating conserved BMP2 synthesis. In summary, our data suggest that transcriptional counter-regulation by GATA4 and LMO3 in LSEC prevents autocrine induction of an inflammatory phenotype, while maintaining angiocrine BMP2-mediated cell communication in the liver vascular niche.

2017-07-13 | GSE100712 | GEO

Gata4 and LMO3 balance angiocrine signaling and autocrine inflammatory activation by BMP2 in liver sinusoidal endothelial cells [HLSEC]

2017-07-13 | GSE100711 | GEO

Identification of factors secreted by testicular germ cell tumor cell lines and microenvironmental cells.

Project description:Type II germ cell tumors (GCTs) are the most common neoplasia in young men of age 14-45 years. It is generally accepted that GCTs arise from a common precursor lesion, called germ cell neoplasia in situ (GCNIS), eventually developing into seminomas or non-seminomas, such as (embryonal carcinomas, ECs). The latter stem-cell like EC can further differentiate into teratomas (TE), yolk-sac tumors (YST), or choriocarcinomas (CC). Even though cisplatin-based chemotherapy is an efficacious standard of care during the management of GCT patients, the development of cisplatin resistance remains a major obstacle. As such, the surrounding tumor microenvironment and its secreted factors could endorse the development of drug resistance. These stromal cells, including immune cells (e.g. macrophages, T-lymphocytes), endothelial cells, and fibroblasts, can influence tumor cells by promoting proliferative and anti-apoptotic signaling pathways. Vice versa, microenvironmental cells can be influenced by tumor cells as well. For the identification of secreted proteins, cell lysates and supernatants from seven human germ cell tumor cell lines (seminoma: TCam-2; embryonal carcinoma (EC): 2102EP, NCCIT; choriocarcinoma (CC): JAR, JEG-3), yolk-sac tumor (YST): GCT72; 1411H) and five human cell types from the microenvironment (fibroblasts: MPAF, HVHF2; M2 macrophages: THP-1-M2; T-lymphocytes: JURKAT; endothelial cells: HUVEC) have been evaluated using liquid chromatography coupled with mass spectrometry (LC-MS).

2022-10-13 | PXD031329 | Pride

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