Disinhibition of Early CAR-T cell activation via CD5 Knock Out Enhances the Anti-Tumor Activity of Adoptive T Cell Therapies against Cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA996645 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25343845.fastq.gz | Fastqsanger.gz | |||
| SRR25343846.fastq.gz | Fastqsanger.gz | |||
| SRR25343847.fastq.gz | Fastqsanger.gz | |||
| SRR25343848.fastq.gz | Fastqsanger.gz | |||
| SRR25343849.fastq.gz | Fastqsanger.gz |
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Project description:The majority of patients treated with currently approved adoptive T-cell therapies (ACT) and, specifically, chimeric antigen receptor (CAR) T cells will eventually fail treatment. Furthermore, ACT has not been successful against solid cancers and several hematological malignancies, including T-cell lymphomas which have extremely poor prognosis. One of the main barriers to the effective activity of adoptively transferred T cells is their inhibition when they reach the tumor bed. In this study, we discover that CD5 inhibits CAR T activation and that the knockout (KO) of CD5 using CRISPR-Cas9 enhances the anti-tumor effect of CAR and TCR T cells in multiple hematological and solid cancer models. As a consequence, CD5 KO T cells display increased in vivo expansion and persistence. Despite this increased activity, no clear increased toxicity was observed in preclinical models. These findings support the development of CD5 KO adoptive T-cell therapies in early-phase clinical trials for relapsed and refractory cancer.
2024-07-18 | GSE237805 | GEO
Project description:The majority of patients treated with currently approved adoptive T-cell therapies (ACT) and, specifically, chimeric antigen receptor (CAR) T cells will eventually fail treatment. Furthermore, ACT has not been successful against solid cancers and several hematological malignancies, including T-cell lymphomas which have extremely poor prognosis. One of the main barriers to the effective activity of adoptively transferred T cells is their inhibition when they reach the tumor bed. In this study, we discover that CD5 inhibits CAR T activation and that the knockout (KO) of CD5 using CRISPR-Cas9 enhances the anti-tumor effect of CAR and TCR T cells in multiple hematological and solid cancer models. As a consequence, CD5 KO T cells display increased in vivo expansion and persistence. Despite this increased activity, no clear increased toxicity was observed in preclinical models. These findings support the development of CD5 KO adoptive T-cell therapies in early-phase clinical trials for relapsed and refractory cancer.
2024-07-18 | GSE248590 | GEO
Project description:Disinhibition of Early T cell Activation via CD5 Knock Out Enhances the Anti-Tumor Activity of Adoptive T Cell Therapies
| PRJNA1044818 | ENA
Project description:Most patients treated with US Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.
| S-EPMC11917452 | biostudies-literature
Project description:CD5 is characterized as an inhibitory co-receptor with important regulatory role during T cell development. To study the molecular mechanism by which CD5 operates, we used quantitative mass spectrometry to analyze the components of the CD5 signaling machinery in primary T cells. In a first set of experiments, CD5-containing complexes were immunoprecipitated from thymocytes of wild-type (WT) C57BL/6 mice. Thymocytes were treated with pervanadate to induce widespread activation of protein tyrosine kinases. Corresponding samples prepared from thymocytes of Cd5−/− mice were used as controls, to discriminate CD5-binding molecules from the background of contaminant proteins. Eight biological replicates were prepared for both conditions, and samples were analyzed in duplicate LC-MS runs. This first set of experiment is presented in TableS1 of the paper, and is associated to the MaxQuant result file “Interactome WT” in the present PX dataset. We analyzed the CD5 interactome at different time of stimulation with pervanadate (1min and 10min) using thymocytes from wild-type (WT) C57BL/6 mice. Corresponding samples prepared from thymocytes of Cd5−/− mice were used as controls. Three biological replicates were prepared for both conditions (WT and KO) and each time point (1min and 10min). This set of experiments is presented in TableS2 of the paper and is associated to the MaxQuant result file “Interactome at 1min and 10min” in the present PX dataset. We checked that the activation of CD5 (phosphorylation sites) and the formation of the signaling complex was comparable in different stimulatory conditions (comparison of WT thymocytes stimulated with either pervanadate or anti-CD3+anti-CD4 antibodies). We also analyzed the binding of CD5 interactors in thymocytes from a c-Cbl-/- mouse model (comparison of WT and c-Cbl-/-thymocytes stimulated with pervanadate). These experiments and the associated experimental design of the comparisons are summarized in TableS3 of the paper, and are based on the MaxQuant result file “Comparison of different stimulatory conditions” in this dataset. To check the phosphorylation status of the CD5 tyrosine residues at different time of stimulation, we analyzed samples immunoprecipitated from thymocytes of wild-type (WT) C57BL/6 mice, following stimulation with anti-CD3+anti-CD4 antibodies for 1min, 3min and 10min. This set of experiment is presented in TableS4 of the paper and is associated to the MaxQuant result file “CD5 pY kinetics” in the present PX dataset. To determine the role of Y429 in the context of CD5 signaling, we expressed a wild-type (CD5tgWt) or a mutated form of CD5, containing a tyrosine to phenylalanine substitution at position 429 (CD5tgY429F) in transgenic mice. We analyzed the CD5 interactome by comparing samples immunoprecipitated from thymocytes of these 2 mice models (following pervanadate stimulation, 6 and 5 biological replicates respectively) with samples prepared in the same way from Cd5−/− mice as controls (6 biological replicates). The results are shown in TableS5 of the paper, and correspond to the MaxQuant result file “interactome CD5tgWt_CD5tgY429F”.
2020-05-18 | PXD017343 | Pride
Project description:We have previously observed that regulatory B cells expressing the apoptosis-inducing surface molecule Fas ligand were enriched in the B cell fraction denoted by a surface phenotype of CD5+CD1dhigh. To identify potential growth factors, transcriptional regulators, or surface markers that might better characterize regulatory B cells, we compared global gene expression by microarray in two B cells subsets isolated by FACS. Splenocytes from 20 DBA/1 male mice were harvested, pooled, and CD19+ B cells were isolated by positive selection using MACS. B cells were then stained for CD5 and CD1d and sorted by FACS into CD5+CD1dhigh and CD5-CD1dhigh populations.
2013-06-30 | GSE46245 | GEO
Project description:We have previously observed that regulatory B cells expressing the apoptosis-inducing surface molecule Fas ligand were enriched in the B cell fraction denoted by a surface phenotype of CD5+CD1dhigh. To identify potential growth factors, transcriptional regulators, or surface markers that might better characterize regulatory B cells, we compared global gene expression by microarray in two B cells subsets isolated by FACS. Splenocytes from 20 DBA/1 male mice were harvested, pooled, and CD19+ B cells were isolated by positive selection using MACS. B cells were then stained for CD5 and CD1d and sorted by FACS into CD5+CD1dhigh and CD5-CD1dhigh populations. Single replicates of both CD5+CD1dhigh and CD5-CD1dhigh B cells from pooled mouse splenocytes were isolated and assay using the Affymetrix GeneChip Mouse 430 2.0 Array.
2013-06-30 | E-GEOD-46245 | biostudies-arrayexpress
Project description:CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) has a poor prognosis and high incidence of central nervous system (CNS) relapse, even in the rituximab era. To determine the gene expression profile of CD5+ DLBCL, total RNA from 90 patients with DLBCL, including 33 CD5+ DLBCL and 57 CD5-negative (CD5-) DLBCL patients, was examined using Agilent human oligo microarrays. These cases were separated into 78 activated B-cell-like (ABC) DLBCLs and 12 germinal center B-cell-like (GCB) DLBCLs. All cases of CD5+ DLBCL were classified as ABC DLBCLs. The classifier based on gene expression used in a supervised analysis correctly identified CD5 expression in the DLBCL and ABC DLBCL samples. The gene most relevant to CD5 expression was SH3BP5. The enriched GO categories in the CD5+ ABC DLBCL signature gene set were multicellular organismal signaling, transmission of nerve impulse, and synaptic transmission. This present study, which includes the largest reported number of patients with CD5+ DLBCL, confirmed that most CD5+ DLBCLs are ABC DLBCLs, suggesting that therapeutic strategies for ABC DLBCL may be effective for the treatment of CD5+ DLBCL. Our CD5+ ABC DLBCL signature gene set may provide insights into the cause of the high frequency of CNS relapse in CD5+ DLBCL.
2015-05-19 | GSE66770 | GEO
Project description:The induction of proinflammatory T cells by dendritic cell (DC) subtypes is critical for anti-tumor responses and effective immune checkpoint blockade (ICB) therapy. Here we show that human CD1c+CD5+ dendritic cells are reduced in melanoma-affected lymph nodes, with CD5 expression on DCs correlating with patient survival. Activating CD5 on DCs enhanced T-cell priming and improved survival after immune checkpoint blockade therapy. CD5+ DC numbers increased during ICB treatment, and low IL-6 levels promoted their de novo differentiation. Mechanistically, CD5 expression by DCs was required to generate optimally protective CD5hi T helper and CD8+ T cells; further, deletion of CD5 from T cells dampened tumor elimination in response to ICB therapy in vivo. Thus, CD5+ dendritic cells are an essential component of optimal immune checkpoint blockade therapy.
2023-02-22 | GSE219197 | GEO
Project description:CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) has a poor prognosis and high incidence of central nervous system (CNS) relapse, even in the rituximab era. To determine the gene expression profile of CD5+ DLBCL, total RNA from 90 patients with DLBCL, including 33 CD5+ DLBCL and 57 CD5-negative (CD5-) DLBCL patients, was examined using Agilent human oligo microarrays. These cases were separated into 78 activated B-cell-like (ABC) DLBCLs and 12 germinal center B-cell-like (GCB) DLBCLs. All cases of CD5+ DLBCL were classified as ABC DLBCLs. The classifier based on gene expression used in a supervised analysis correctly identified CD5 expression in the DLBCL and ABC DLBCL samples. The gene most relevant to CD5 expression was SH3BP5. The enriched GO categories in the CD5+ ABC DLBCL signature gene set were multicellular organismal signaling, transmission of nerve impulse, and synaptic transmission. This present study, which includes the largest reported number of patients with CD5+ DLBCL, confirmed that most CD5+ DLBCLs are ABC DLBCLs, suggesting that therapeutic strategies for ABC DLBCL may be effective for the treatment of CD5+ DLBCL. Our CD5+ ABC DLBCL signature gene set may provide insights into the cause of the high frequency of CNS relapse in CD5+ DLBCL. This present study involved 90 cases (33 patients with CD5+ DLBCL and 57 with CD5- DLBCL) of de novo consecutive DLBCL diagnosed at Mie University Hospital with available frozen biopsy specimens and total RNA samples. Lymphoma tissue RNA from 90 patients was extracted for target preparation and hybridization onto Agilent microarrays. The expression of CD5 in tumor cells was confirmed by means of immunohistochemistry using frozen sections.
2015-05-19 | E-GEOD-66770 | biostudies-arrayexpress