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CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment

ABSTRACT: CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment

PROVIDER: PRJNA755710 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15503336.fastq.gz	Fastqsanger.gz
	SRR15503337.fastq.gz	Fastqsanger.gz
	SRR15503338.fastq.gz	Fastqsanger.gz
	SRR15503339.fastq.gz	Fastqsanger.gz
	SRR15503340.fastq.gz	Fastqsanger.gz

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Similar Datasets

CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment

Project description:We have used our established Glioblastoma cell models and gene expression analyses to characterize gene wild-type and CD70 knockdown GBM cell lines

2022-09-01 | GSE182295 | GEO

CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment.

Project description:PurposeGlioblastoma (GBM) patients suffer from a dismal prognosis, with standard of care therapy inevitably leading to therapy-resistant recurrent tumors. The presence of cancer stem cells (CSCs) drives the extensive heterogeneity seen in GBM, prompting the need for novel therapies specifically targeting this subset of tumor-driving cells. Here, we identify CD70 as a potential therapeutic target for recurrent GBM CSCs.Experimental designIn the current study, we identified the relevance and functional influence of CD70 on primary and recurrent GBM cells, and further define its function using established stem cell assays. We use CD70 knockdown studies, subsequent RNAseq pathway analysis, and in vivo xenotransplantation to validate CD70's role in GBM. Next, we developed and tested an anti-CD70 chimeric antigen receptor (CAR)-T therapy, which we validated in vitro and in vivo using our established preclinical model of human GBM. Lastly, we explored the importance of CD70 in the tumor immune microenvironment (TIME) by assessing the presence of its receptor, CD27, in immune infiltrates derived from freshly resected GBM tumor samples.ResultsCD70 expression is elevated in recurrent GBM and CD70 knockdown reduces tumorigenicity in vitro and in vivo. CD70 CAR-T therapy significantly improves prognosis in vivo. We also found CD27 to be present on the cell surface of multiple relevant GBM TIME cell populations, notably putative M1 macrophages and CD4 T cells.ConclusionCD70 plays a key role in recurrent GBM cell aggressiveness and maintenance. Immunotherapeutic targeting of CD70 significantly improves survival in animal models and the CD70/CD27 axis may be a viable polytherapeutic avenue to co-target both GBM and its TIME.

| S-EPMC8753449 | biostudies-literature

Analysis of CD70 wild type or CD70 knock out CD70-specific nanoCAR T cells

Project description:CD70 is an attractive target for chimeric antigen receptor (CAR) T cell therapy as treatment for both solid and liquid malignancies. However, functionality of CD70-specific CAR T cells is only modest. Here, we optimized a CD70-specific VHH based CAR (nanoCAR). We evaluated the nanoCARs in clinically relevant models in vitro, using co-cultures of CD70-specific nanoCAR T cells with malignant rhabdoid tumor organoids, and in vivo by using a diffuse large B cell lymphoma (DLBCL) patient-derived xenograft (PDX) model. Whereas the nanoCAR T cells were highly efficient in organoid co-cultures, they showed only modest efficacy in the PDX model. Knocking out CD70 expression in the nanoCAR T cells resulted in dramatically enhanced functionality in the PDX model, suggesting that CD70 interaction in cis with the nanoCAR induces exhaustion. Through single-cell transcriptomics, we obtained evidence that CD70 KO CD70-specific nanoCAR T cells are protected from antigen-induced exhaustion. Our data show that CARs targeted to endogenous T cell antigens, negatively affect CAR T cell functionality by inducing an exhausted state, which can be overcome by knocking out the specific target, in this case CD70.

2024-06-17 | GSE227435 | GEO

Analysis of CD70 wild type or CD70 knock out CD70-specific nanoCAR T cells [RNA-Seq]

Project description:CD70 is an attractive target for chimeric antigen receptor (CAR) T-cell therapy for the treatment of both solid and liquid malignancies. However, the functionality of CD70-specific CAR T-cells is modest. We optimized a CD70-specific VHH-based CAR (nanoCAR). We evaluated the nanoCARs in clinically relevant models in vitro, using co-cultures of CD70-specific nanoCAR T-cells with malignant rhabdoid tumor organoids, and in vivo using a diffuse large B-cell lymphoma (DLBCL) patient-derived xenograft (PDX) model. Whereas the nanoCAR T-cells were highly efficient in organoid co-cultures, they showed only modest efficacy in the PDX model. Fratricide was not causing this loss in efficacy but rather CD70 interaction in cis with the nanoCAR, as validated by imaging flowcytometry, induces exhaustion. Knocking out CD70 expression in nanoCAR T-cells using CRISPR/Cas9, resulted in dramatically enhanced functionality in the DLBCL PDX model. Through single-cell transcriptomics, we obtained evidence that CD70 knock out (KO) CD70-specific nanoCAR T-cells were protected from antigen-induced exhaustion. In addition, we were able to demonstrate that WT CD70-specific nanoCAR T-cells already exhibit signs of exhaustion shortly after production. Their gene signature strongly overlapped with gene signatures of exhausted CAR T-cells. On the other hand, the gene signature of KO nanoCAR T-cells overlapped with the gene signature of CAR T-cell infusion products that led to complete responses in chronic lymphatic leukemia patients. Our data show that CARs targeting endogenous T-cell antigens, negatively affect CAR T-cell functionality by inducing an exhausted state, which can be overcome by knocking out the specific target, in this case CD70.

2024-06-17 | GSE265937 | GEO

Analysis of CD70 wild type or CD70 knock out CD70-specific nanoCAR T cells

Project description:Analysis of CD70 wild type or CD70 knock out CD70-specific nanoCAR T cells

| PRJNA945042 | ENA

RNA sequencing analysis of ex vivo expanded CD27+CD70- and CD27-CD70+ human regulatory T cells

Project description:Our study shows that after extended stimulation of human CD4+CD25+CD127- Tregs in vitro, a stable cell subset that downregulates CD27 and upregulates CD70 develops. Expanded CD27+CD70- Tregs display a gene profile which closely relates to the previously described “Treg gene signature”, whereas CD27-CD70+ Tregs express some genes associated with Treg gene signature and some genes overexpressed in conventional T cells.

2020-07-10 | GSE129251 | GEO

Analysis of CD70 wild type or CD70 knock out CD70-specific nanoCAR T cells [RNA-Seq]

Project description:Analysis of CD70 wild type or CD70 knock out CD70-specific nanoCAR T cells [RNA-Seq]

| PRJNA1105004 | ENA

Clostridioides difficile CD70

Project description:Clostridioides difficile CD70 Genome sequencing and assembly

| PRJNA85723 | ENA

CD70 identifies donor derived alloreactive T cells in severe acute Graft vs Host Disease post allogeneic SCT

Project description:Graft-versus-host disease (GvHD) remains a major challenge post allogeneic hematopoietic stem cell transplantation (allo-HSCT) and understanding its immunopathology is crucial for effective therapeutic intervention. Here we investigated the significance of CD70, a co-stimulatory molecule, in the context of aGvHD. CD70 was found to be transiently expressed on activated T cells during early immune reconstitution post-transplantation but persisted longer in aGvHD. Our findings illustrate that CD70+ T cells are characterized by upregulated activation receptors and enhanced cytokine production, while displaying signs of exhaustion. Remarkably, CD70+ T cells expressed chemokine receptors CCR4 and CCR6 and were actively recruited to inflamed tissues, implicating them in aGvHD pathogenesis. The chromatin at transcription factor MGA and NFAT5 loci was found to be selectively altered upon allo-antigenic stimulation in CD70+ T cells ex-vivo. Gene transcriptions of Toll-like receptors and MAPK signalling pathway were also found to differ in CD70+ and CD70- T cells of aGvHD patients. Insights into the clonality and antigen specificity of CD70+ T cell populations revealed potential novel antigenic targets. Further blocking CD70 in allogeneic T cells from aGvHD patients primed with autologous antigen presenting cells prior to HSCT demonstrated that anti-CD70 antibody reduced T cell proliferation and cytokine production. These findings implicate CD70 as a potential therapeutic target to modulate T cell responses and mitigate aGvHD. Targeting the CD70-CD27 co-stimulation pathway holds promise for prophylactic treatment.

2024-10-02 | GSE247452 | GEO

POSTN secreted from glioblastoma stem cells can recruit microglia and upregulate CD70 expression in microglia through the αVβ3/PI3K/AKT/NFκB pathway

Project description:Our findings revealed that POSTN secreted from GSCs can recruit microglia and upregulate CD70 expression in microglia through the αVβ3/PI3K/AKT/NFκB pathway, which in turn promotes Treg development and functionality and supports the formation of an immunosuppressive tumor microenvironment.

2024-08-04 | GSE273464 | GEO

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