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A multimodal assay identifies optimized binders for a bicistronic CAR against GPC2 OR CD276 to overcome heterogeneity in Neuroblastoma

ABSTRACT: A multimodal assay identifies optimized binders for a bicistronic CAR against GPC2 OR CD276 to overcome heterogeneity in Neuroblastoma

PROVIDER: PRJNA752052 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15341776.fastq.gz	Fastqsanger.gz
	SRR15341777.fastq.gz	Fastqsanger.gz
	SRR15341778.fastq.gz	Fastqsanger.gz
	SRR15341779.fastq.gz	Fastqsanger.gz
	SRR15341780.fastq.gz	Fastqsanger.gz

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A multimodal assay identifies optimized binders for a bicistronic CAR against GPC2 OR CD276 to overcome heterogeneity in Neuroblastoma

Project description:Neuroblastoma (NB) is the most common extra-cranial solid tumor in children and remains deadly in patients with high-risk disease. Single chimeric antigen receptor T-cell therapies (CAR-T) for solid tumor have shown poor efficacy in clinical trials due, in part, to T cell exhaustion and uneven expression of target antigens in tumors. Here, we attempted to target Glypican-2(GPC2) and CD276(B7-H3), both highly but heterogeneously expressed on NB cell surface, to overcome these challenges in single CAR T- therapies. First, to identify optimal binders for CAR T- cell targeting each antigen, we made individual CAR constructs using multiple binders against these antigens and utilized a multimodal approach including simultaneous protein and transcriptome measurement at single cell level to characterize each individual CAR T- cell in a pooled strategy. Combined with cell expansion and cytotoxicity assays, we identified the most effective CAR construct for each target.

2022-03-18 | GSE181437 | GEO

Multimodal single-cell profiling reveals the enhanced antitumor activity of FGFR4/CD276 BiCisCAR T cells in rhabdomyosarcoma

Project description:We have generated a clinical grade CAR T targeting FGFR4 with a CD8 hinge and transmembrane domain (HTM) and a 4-1BB co-stimulatory domain (CSD) that is currently being developed for a clinical trial at the NCI. This standard FGFR4-CAR demonstrated potency in low burden RMS disease but has a more modest effect for bulky disease in RMS orthotopic model. Thus, we developed optimized FGFR4-CARs by modification of HTM or CSD to improve its efficacy. However, these modified FGFR4-CARs, even FGFR4.28HTM.28z CAR were unable to eradicate solid tumors in an more aggressive RMS559 model. CAR T cells targeting another cell surface protein CD276, a direct target of the RMS core-regulatory transcription factor MYOD1 is potent and effective, also could not eradicate the tumor. Therefore, we engineered a bicistronic CAR (BiCisCAR) to target both FGFR4 and CD276, with CD28 and 4-1BB CSDs, respectively, which showed remarkable and rapid tumor eradication compared with either single CAR alone. Here, we utilized a multimodal approach including simultaneous protein and transcriptome measurement at single cell level to characterize each FGFR4 or CD276 CAR T-cell infiltrating in RMS orthotopic xenografts. This assay further determined the molecular basis of superior antitumor effect of FGFR4.28HTM.28z-CD276.8HTM.BBz BiCisCAR T cells compared with other CARs.

2024-05-23 | GSE228127 | GEO

RNA-seq analysis of CD276-high/EpCAM+ cells from HNSCC patient-derived-xenograft

Project description:We performed RNA sequencing (RNA-seq) to compare the gene expression pattern between CD276-high/EpCAM+ and CD276-low/EpCAM+ cells isolated from human HNSCC PDX. We identified a cohort of key oncogenes associate with cancer stemness enriched in CD276-high cells. Suggesting CD276 may play a positive role in maintaining cancer stem cells in human head and neck squamous cell carcinoma.

2021-05-28 | GSE132627 | GEO

CD276 is an important player in macrophage recruitment into the tumor and an upstream regulator for PAI-1

Project description:70-100% of colorectal, prostate, ovarian, pancreatic and breast cancer specimens show expression of CD276 (B7-H3), a potential immune checkpoint family member. Several studies have shown that high CD276 expression in cancer cells correlates with a poor clinical prognosis. This has been associated with the presence of lower tumor infiltrating leukocytes. Among those, tumor-associated macrophages can comprise up to 50% of the tumor mass and are thought to support tumor growth through various mechanisms. However, a lack of information on CD276 function and interaction partner(s) impedes rigorous evaluation of CD276 as a therapeutic target in oncology. Therefore, we aimed to understand the relevance of CD276 in tumor-macrophage interaction by employing a 3D spheroid coculture system with human cells. Our data show a role for tumor-expressed CD276 on the macrophage recruitment into the tumor spheroid, and also in regulation of the extracellular matrix modulator PAI-1. Furthermore, our experiments focusing on macrophage-expressed CD276 suggest that the antibody-dependent CD276 engagement triggers predominantly inhibitory signaling networks in human macrophages.

2021-07-28 | GSE165610 | GEO

Multimodal single-cell profiling reveals the enhanced antitumor activity of FGFR4/CD276 BiCisCAR T cells in rhabdomyosarcoma

Project description:Multimodal single-cell profiling reveals the enhanced antitumor activity of FGFR4/CD276 BiCisCAR T cells in rhabdomyosarcoma

| PRJNA948361 | ENA

Identification of Cpeb4 binders in cardiomyocyte

Project description:Identification of Cpeb4 binders in cardiomyocyte

| PRJNA642364 | ENA

Innate immune response to G-quadruplex binders in cancer cells

Project description:G-quadruplex (G4) is non-canonical nucleic acid structure involved in a plethora of fundamental biological processes. In past decades, it has been studied as a promising pharmaceutical target for anticancer therapy. However, no G4-targeting agent has shown significant clinical effects up to date. Pyridostatin (PDS), a well-known G4 binder, can induce double-stranded DNA breaks and genome instability. We have recently shown that Pyridostatin (Pyridostatin) and other G4 binders can trigger micronuclei formation in cancer cells at non-cytotoxic concentrations. As micronuclei can play a crucial role in linking genome instability to innate immunity, we have here wondered whether G4 binders can induce immune gene activation in human MCF-7 breast cancer cells.

2021-07-14 | GSE161418 | GEO

Multimodal chromatin profiling using nanobody-based single-cell CUT&Tag

Project description:Probing epigenomic marks such as histone modifications at a single cell level in thousands of cells has been recently enabled by technologies such as scCUT&Tag. Here we developed a multimodal and optimized iteration of scCUT&Tag called nano-CT (for nano-CUT&Tag) that allows simultaneous probing of three epigenomic modalities at single-cell resolution, using nanobody-Tn5 fusion proteins. nano-CT is compatible with starting materials as low as 25 000 cells and has significantly higher resolution than scCUT&Tag, with a 16-fold increase in the number of fragments per cells. We used nano-CT to simultaneously profile chromatin accessibility, H3K27ac and H3K27me3 in a complex tissue - juvenile mouse brain. The obtained multimodal dataset allowed for discrimination of more cell types/states that scCUT&Tag, and inference of chromatin velocity between ATAC and H3K27ac in the oligodendrocyte (OL) lineage. In addition, we used nano-CT to deconvolute H3K27me3 repressive states and infer two sequential waves of H3K27me3 repression at distinct gene modules during OL lineage progression. Thus, given its high resolution, versatility, and multimodal features, nano-CT allows unique insights in epigenetic landscapes in different biological systems at single cell level.

2022-09-20 | GSE198467 | GEO

A Dual-Payload Antibody-Drug Conjugate Targeting CD276/B7-H3 Elicits Cytotoxicity and Immune Activation in Triple-Negative Breast Cancer

Project description:Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous disease that often relapses following treatment with standard radiotherapies and cytotoxic chemotherapies. Combination therapies have potential for treating refractory metastatic TNBC. Here, we aimed to develop an antibody-drug conjugate with dual payloads (DualADC) as a chemo-immunotherapy for TNBC. The overexpression of an immune checkpoint transmembrane CD276 (also known as B7-H3) was associated with angiogenesis, metastasis, and immune tolerance, in over 60% of TNBC patients. Development of a monoclonal antibody (mAb) capable of targeting the extracellular domain of surface CD276 enabled delivery of payloads to tumors, and a platform was established for concurrent conjugation of a traditional cytotoxic payload and an immunoregulating toll-like receptor 7/8 agonist to the CD276 mAb. The DualADC effectively killed multiple TNBC subtypes, significantly enhanced immune functions in the tumor microenvironment, and reduced tumor burden by up to 90-100% in animal studies. Single-cell RNA-sequencing, multiplex cytokine analysis, and histology elucidated the impact of treatment on tumor cells and the immune landscape. This study suggests that the developed DualADC could represent a promising targeted chemo-immunotherapy for TNBC.

2024-08-21 | GSE274871 | GEO

Single-cell Sequencing Analysis Identifies Intratumoral Cell Population in Head and Neck Squamous Cell Carcinoma from 4NQO-induced Mice upon anti-CD276 Therapy

Project description:In this study, we aimed to identifies the landscape alterations of intratumoral cell population in HNSCC from 4NQO-induced mice upon anti-CD276 treatment by using single cell sequencing analysis.we characterized the alterations of intratumoral cell population by separating cancer cells and yielded 6 distinct cancer cell subpopulations defined by the transcriptional state of cells and known marker genes, including the sunpopulation with pEMT, stress, typical epithelial differentiation, high cell-cycling, metabolism and immune fetures. In response of CD276 treatment, the frequecey of cells with pEMT, cell cycling and immune features are dcreased as compared to the vehicle control mice.

2021-05-28 | GSE164817 | GEO

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