Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

OR7A10 GPCR engineering boosts CAR-NK therapy against solid tumors

ABSTRACT: Chimeric antigen receptor (CAR)-natural killer (NK) cell therapies hold promise for solid tumors but remain limited by poor tumor infiltration, persistence, and resistance within the tumor microenvironment (TME). To identify gain-of-function (GOF) targets that enhance CAR-NK efficacy, we performed an unbiased in vivo Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) activation (CRISPRa) screen, followed by a barcoded targeted in vivo open reading frame (ORF) screen in primary human CAR-NK cells. We identified, and robustly validated OR7A10, , a G protein-coupled receptor (GPCR), as the top candidate. Engineering CAR-NKs with OR7A10 cDNA, a CRISPR-independent method with simple manufacturing strategy, enhanced proliferation, activation, degranulation, cytokine production, death ligand expression, chemokine receptor expression, cytotoxicity, persistence, metabolic fitness, and TME resistance, while reducing exhaustion in primary human NK cells derived from multiple peripheral blood and cord blood donors. OR7A10-GOF CAR-NKs displayed robust in vivo efficacy across multiple solid tumor models, achieving a 100% complete response in an orthotopic breast cancer model with long term tumor control and survival benefit. These findings establish OR7A10-engineered CAR-NKs as a highly potent and scalable off-the-shelf therapeutic for solid tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310267 | GEO | 2025/12/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

OR7A10 GPCR engineering boosts CAR-NK therapy against solid tumors [scRNA-Seq]

Project description:Chimeric antigen receptor (CAR)-natural killer (NK) cell therapies hold promise for solid tumors but remain limited by poor tumor infiltration, persistence, and resistance within the tumor microenvironment (TME). To identify gain-of-function (GOF) targets that enhance CAR-NK efficacy, we performed an unbiased in vivo Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) activation (CRISPRa) screen, followed by a barcoded targeted in vivo open reading frame (ORF) screen in primary human CAR-NK cells. We identified, and robustly validated OR7A10, , a G protein-coupled receptor (GPCR), as the top candidate. Engineering CAR-NKs with OR7A10 cDNA, a CRISPR-independent method with simple manufacturing strategy, enhanced proliferation, activation, degranulation, cytokine production, death ligand expression, chemokine receptor expression, cytotoxicity, persistence, metabolic fitness, and TME resistance, while reducing exhaustion in primary human NK cells derived from multiple peripheral blood and cord blood donors. OR7A10-GOF CAR-NKs displayed robust in vivo efficacy across multiple solid tumor models, achieving a 100% complete response in an orthotopic breast cancer model with long term tumor control and survival benefit. These findings establish OR7A10-engineered CAR-NKs as a highly potent and scalable off-the-shelf therapeutic for solid tumors.

2025-12-17 | GSE309799 | GEO

OR7A10 GPCR engineering boosts CAR-NK therapy against solid tumors [mini screen]

2025-12-17 | GSE309801 | GEO

OR7A10 GPCR engineering boosts CAR-NK therapy against solid tumors [Primary Screen]

2025-12-17 | GSE309800 | GEO

IPSC-Derived CAR-NK Extracellular Vesicles Remodel Macrophage Immunity and Enhance Tumor Eradication

Project description:Chimeric antigen receptor (CAR) cell therapy has revolutionized the treatment of hematological malignancies; however, its efficacy in solid tumors remains limited due to dense stromal barriers and the immunosuppressive tumor microenvironment (TME), which hinder immune cell infiltration and persistence. To overcome these challenges, we propose an innovative strategy utilizing induced pluripotent stem cell (iPSC)-derived CAR-NK extracellular vesicles (CAR-iNEV), engineered from iPSC-differentiated NK cells. Unlike conventional CAR-NK cell therapies that rely on immortalized NK92 cell lines, our approach leverages iPSC-derived NK cells, reducing tumorigenic risk and enhancing CAR transduction efficiency. Additionally, we incorporate nanobody-based CAR constructs in place of traditional single-chain variable fragments (scFv), significantly improving CAR stability and expression efficiency. Beyond direct cytotoxicity, CAR-iNEV offers superior therapeutic advantages, including reduced systemic toxicity and enhanced drug delivery capabilities compared to CAR-iNK cells. In vivo studies demonstrate that CAR-iNEV exhibits exceptional safety and potent antitumor activity across multiple solid tumor xenograft and patient-derived xenograft (PDX) models in humanized mice. Mechanistically, CAR-iNEV not only directly eliminates tumor cells but also reprograms the TME by activating macrophage-derived nitric oxide synthase (NOS2), amplifying host antitumor immunity. These findings establish CAR-iNEV as a promising platform for solid tumor immunotherapy, particularly in relapsed and metastatic settings, providing a novel and effective strategy that bridges direct tumor targeting with immune microenvironment remodeling. This study lays the foundation for future clinical translation, advancing the next generation of cell-free CAR-based immunotherapies.

2025-11-26 | GSE293929 | GEO

Reprogramming the neuroblastoma tumor immune microenvironment to enhance GPC2 CAR T cells

Project description:Poor tumor trafficking and the immunosuppressive tumor microenvironment (TME) limit chimeric antigen receptor (CAR) T cell efficacy in solid tumors, such as neuroblastoma. We previously optimized GPC2 CARs in human neuroblastoma xenografts leading to clinical translation, however, there have not been preclinical studies using immunocompetent models. Thus, here we generated murine GPC2 CAR T cells using the D3-GPC2-targeting single-chain variable fragment being utilized clinically (NCT05650749) and tested them in neuroblastoma syngeneic allografts. Immune profiling of GPC2 CAR T cell-treated tumors revealed significant reprogramming of the TME, most notably poor intra-tumor CAR T cell persistence being associated with increased recruitment of myeloid-derived suppressor cells (MDSCs), along with MDSC-recruiting CXCL1/2 chemokines. These tumor-infiltrating MDSCs directly inhibited GPC2 CAR T cell activation and proliferation ex vivo. To both capitalize on this chemokine gradient and mitigate MDSC-tumor trafficking, we engineered GPC2 CAR T cells to express the CXCL1/2 receptor, CXCR2. CXCR2-armored GPC2 CAR T cells migrated towards CXCL1/2 gradients, enhanced anti-neuroblastoma efficacy, and reduced the level of MDSCs in the TME. Together, these findings suggest CAR T cell studies in immunocompetent models are imperative to define mechanisms of solid tumor immune escape and rationally design armoring strategies that will lead to durable clinical efficacy.

2025-09-17 | GSE295013 | GEO

Tumor-site directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors. [CD8 inducible human RNAseq]

Project description:The efficacy of Chimeric Antigen Receptor (CAR) T cells against solid tumors is limited by immunosuppressive factors in the tumor microenvironment (TME) including adenosine, which suppresses CAR T cells through activation of the A2A receptor (A2AR). To overcome this, CAR T cells were engineered to express A1 receptor (A1R), a receptor that signals inversely to A2AR. Using murine and human CAR T cells, constitutive A1R overexpression was demonstrated to significantly enhance CAR T cell effector function albeit at the expense of CAR T cell persistence. Through a novel CRISPR/Cas9 “knock-in” approach we demonstrated that CAR T cells engineered to express A1R in a tumor-localized manner, led to enhanced anti-tumor efficacy dependent on the transcription factor IRF8 and was transcriptionally unique when compared to A2AR deletion. This data provides a novel approach for enhancing CAR T cell efficacy in solid tumors and provides proof of principle for site-directed expression of factors that promote effector T cell differentiation.

2025-03-16 | GSE284619 | GEO

Tumor-site directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors. [Human RNAseq inducible]

2025-03-16 | GSE284618 | GEO