Gene expression profiles of CAR-T cells engineered with chimeric cytokine receptors to induce JAK-STAT signaling
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ABSTRACT:
PROVIDER: PRJNA1073839 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27885908_1.fastq.gz | Fastqsanger.gz | |||
| SRR27885908_2.fastq.gz | Fastqsanger.gz | |||
| SRR27885909_1.fastq.gz | Fastqsanger.gz | |||
| SRR27885909_2.fastq.gz | Fastqsanger.gz | |||
| SRR27885910_1.fastq.gz | Fastqsanger.gz |
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Project description:Cytokines augment T cell function, but the nature of the optimal signals are not well defined. We deployed orthogonal cytokine-receptors to diversify the JAK/STAT signaling profiles elicited by orthogonal IL-2. We designed chimeric receptors consisting of the orthogonal IL-2 receptor extracellular domain (ECD) fused to intracellular domains (ICDs) from receptors for other common gamma chain cytokines as well as ICDs from interferon receptor, IL-10 receptor and homodimeric receptor families not expressed on T cells. Such non-natural pairings with the common gamma chain expand the JAK/STAT signaling space in T cells. Natural and non-natural orthogonal chimeric receptors led to distinct T cell fates in tumors, including naturally occurring states (Tc2 differentiation driven by orthogonal chimeric IL4R) and synthetic states (myeloid-like T cells driven by orthogonal chimeric granulocyte colony stimulating factor receptor). The orthogonal chimeric IL22R (o22R) potently activated STAT-1, -3, -4, and -5, imparting T cells with stem-like and effector properties. The pronounced anti-tumor functionality mediated by o22R and oGCSFR was linked to remodeling of the exhaustion-associated epigenome. Our study broadens the cytokine receptor repertoire, providing novel solutions to overcome barriers for using engineered T cells to treat cancer.
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Project description:Purpose: analyze ligand and receptor genes regulated at early time points following JAK STAT pathway stimulation During development and homeostasis, cells integrate multiple signals originating either from neighboring cells or systemically. In turn, responding cells can produce signals that act in an autocrine, paracrine, or endocrine manner. Although the nature of the signals and pathways used in cell-cell communication are well characterized, we lack, in most cases, an integrative view of signaling describing the spatial and temporal interactions between pathways (e.g., whether the signals are processed sequentially or concomitantly when two pathways are required for a specific outcome). To address the extent of cross-talk between the major metazoan signaling pathways, we characterized immediate transcriptional responses to either single- or multiple pathway stimulations in homogeneous Drosophila cell lines. Our study, focusing on seven core pathways, epidermal growth factor receptor (EGFR), bone morphogenetic protein (BMP), Jun kinase (JNK), JAK/STAT, Notch, Insulin, and Wnt, revealed that many ligands and receptors are primary targets of signaling pathways, highlighting that transcriptional regulation of genes encoding pathway components is a major level of signaling cross-talk. In addition, we found that ligands and receptors can integrate multiple pathway activities and adjust their transcriptional responses accordingly. RNA-seq data is for JAK STAT pathway only
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Project description:Here we investigated the effects of JAK/STAT pharmacological inhibition on cHL cell models using ruxolitinib, a JAK 1/2 inhibitor. We use five classical Hodgkin lymphoma cell lines: L428, L1236, L540, KMH2, L591
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Project description:The efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy is suboptimal in most of the cancer types , necessitating further improvement in their therapeutic actions. However, enhancing antitumor T cell response inevitably confers an increased risk of cytokine release syndrome associated with monocyte-derived IL-6 secretion. Thus, a novel approach to simultaneously enhance therapeutic efficacy and safety is warranted. In this study, we developed a chimeric cytokine receptor composed of the extracellular domains of GP130 and IL6RA linked to the transmembrane and cytoplasmic domain of IL-7R mutant that constitutively activate JAK-STAT pathway (G6/7R). CAR-T cells with G6/7R efficiently absorbed and degraded monocyte-derived IL-6 both in vitro and in vivo. The G6/7R-expressing CAR-T cells showed superior expansion and persistence in vivo, which resulted in durable antitumor response in multple tumor models. Our strategy can be widely applicable to CAR-T cell therapy to enhance its efficacy and safety, irrespective of the target antigen.
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Project description:Immune cells need to sustain a state of constant alertness over a lifetime. Yet, little is known about the regulatory processes that control the fluent and fragile balance that is called homeostasis. Here we demonstrate that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. We investigated JAK-STAT-mediated transcription and chromatin accessibility across 12 mouse models, including knockouts of all STAT transcription factors and of the TYK2 kinase. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice – but abrogated in the knockouts and in unstimulated immune cells deprived of their normal tissue context. We observed diverse transcription-regulatory programs, including gene regulation by STAT2 and IRF9 independent of STAT1. In summary, our large-scale dataset and integrative analysis of JAK-STAT mutant and wildtype mice uncovered a crucial role of JAK-STAT signaling in unstimulated immune cells, where it contributes to a poised epigenetic and transcription-regulatory state and helps prepare these cells for rapid response to immune stimuli.
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Project description:Immune cells need to sustain a state of constant alertness over a lifetime. Yet, little is known about the regulatory processes that control the fluent and fragile balance that is called homeostasis. Here we demonstrate that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. We investigated JAK-STAT-mediated transcription and chromatin accessibility across 12 mouse models, including knockouts of all STAT transcription factors and of the TYK2 kinase. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice – but abrogated in the knockouts and in unstimulated immune cells deprived of their normal tissue context. We observed diverse transcription-regulatory programs, including gene regulation by STAT2 and IRF9 independent of STAT1. In summary, our large-scale dataset and integrative analysis of JAK-STAT mutant and wildtype mice uncovered a crucial role of JAK-STAT signaling in unstimulated immune cells, where it contributes to a poised epigenetic and transcription-regulatory state and helps prepare these cells for rapid response to immune stimuli.
2024-02-24 | GSE227168 | GEO
Project description:Immune cells need to sustain a state of constant alertness over a lifetime. Yet, little is known about the regulatory processes that control the fluent and fragile balance that is called homeostasis. Here we demonstrate that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. We investigated JAK-STAT-mediated transcription and chromatin accessibility across 12 mouse models, including knockouts of all STAT transcription factors and of the TYK2 kinase. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice – but abrogated in the knockouts and in unstimulated immune cells deprived of their normal tissue context. We observed diverse transcription-regulatory programs, including gene regulation by STAT2 and IRF9 independent of STAT1. In summary, our large-scale dataset and integrative analysis of JAK-STAT mutant and wildtype mice uncovered a crucial role of JAK-STAT signaling in unstimulated immune cells, where it contributes to a poised epigenetic and transcription-regulatory state and helps prepare these cells for rapid response to immune stimuli.
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Project description:Although the JAK/STAT pathway regulates numerous processes in vertebrates and invertebrates through modulating transcription, its functionally-relevant transcriptional targets remain largely unknown. With one jak and one stat (stat92E), Drosophila provides a powerful system for finding new JAK/STAT target genes. Genome-wide expression profiling on eye discs in which Stat92E is hyperactivated, revealed 584 differentially-regulated genes, including known targets domeless, socs36E and wingless. Other differentially-regulated genes (chinmo, lama, Mo25, Imp-L2, Serrate, Delta) were validated and may represent new Stat92E targets. Genetic experiments revealed that Stat92E cell-autonomously represses Serrate, which encodes a Notch ligand. Loss of Stat92E led to de-repression of Serrate in the dorsal eye, resulting in ectopic Notch signaling and aberrant eye growth there. Thus, our micro-array documents a new Stat92E target gene and a previously-unidentified inhibitory action of Stat92E on Notch signaling. These data suggest that this study will be a useful resource for the identification of additional Stat92E targets. Identification of the JAK/STAT pathway target genes in the Drosophila eye disc Keywords: Genotype comparison Gene expression profiles from five biological replicates of eye discs with yw (control) and GMR-upd (overexpressing JAK/STAT ligand unpaired) were compared using genome wide mRNA expression profiling by Affymetrix genechip arrays (Drosophila 2.0) and key targets were validated by clonal analysis, in situ hybridization, immunohistochemical staining and quantitative real-time PCR.
2009-08-01 | E-GEOD-15868 | biostudies-arrayexpress