Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1104636 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28803792_1.fastq.gz | Fastqsanger.gz | |||
| SRR28803792_2.fastq.gz | Fastqsanger.gz | |||
| SRR32938604.fastq.gz | Fastqsanger.gz |
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Project description:A STUB1-CHIC2 complex decreases IL-27Rα expression on CD8+ T cells to restrain tumor immunity
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Project description:A STUB1-CHIC2 complex decreases IL-27Rα expression on CD8+ T cells to restrain tumor immunity [RNAseq_STUB1KO]
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Project description:CRISPR screens in CD8+ T cells have uncovered novel immunotherapy targets for cancer; however, these screens used activated CD8+ T cells, precluding identification of genes regulating CD8+ T cell priming in the tumor-draining lymph (tdLN). Here we present an 899-gene in vivo CRISPR screen in naive CD8+ T cells, which identifies novel regulators of CD8+ T cell responses in the tdLN and tumor. We find that STUB1, an E3 ubiquitin ligase, significantly regulates CD8+ T cell accumulation in both tissues and Stub1 knockout (KO) CD8+ T cells improve tumor growth control. Mechanistically, STUB1 interacts with the adapter protein, CHIC2, to regulate IL-27Rα, which is required for the increased anti-tumor responses of Stub1 and Chic2 KO CD8+ T cells. Overall, these findings demonstrate that the STUB1-CHIC2 complex is a novel regulator of cytokine receptor expression in CD8+ T cells and provide the rationale for inhibiting this pathway to improve CD8+ T cell-mediated anti-tumor immunity.
2025-08-12 | PXD049402 | Pride
Project description:CRISPR screens in CD8+ T cells have uncovered novel immunotherapy targets for cancer; however, these screens used activated CD8+ T cells, precluding identification of genes regulating CD8+ T cell priming in the tumor-draining lymph (tdLN). Here we present an 899-gene in vivo CRISPR screen in naive CD8+ T cells, which identifies novel regulators of CD8+ T cell responses in the tdLN and tumor. We find that STUB1, an E3 ubiquitin ligase, significantly regulates CD8+ T cell accumulation in both tissues and Stub1 knockout (KO) CD8+ T cells improve tumor growth control. Mechanistically, STUB1 interacts with the adapter protein, CHIC2, to regulate IL-27Rα, which is required for the increased anti-tumor responses of Stub1 and Chic2 KO CD8+ T cells. Overall, these findings demonstrate that the STUB1-CHIC2 complex is a novel regulator of cytokine receptor expression in CD8+ T cells and provide the rationale for inhibiting this pathway to improve CD8+ T cell-mediated anti-tumor immunity.
2025-08-12 | PXD062475 | Pride
Project description:In vivo CRISPR screens using activated CD8+ T cells have uncovered novel immunotherapy targets for cancer, yet similar high-throughput screens have not been performed using naive CD8+ T cells. Here we present an 899-gene in vivo CRISPR screen using naive CD8+ T cells, which identified the E3 ubiquitin ligase STUB1 as a novel negative regulator of anti-tumor CD8+ T cell responses. Stub1 knockout (KO) CD8+ T cells control tumor growth across multiple murine models. Mechanistically, STUB1 interacts with the adapter protein CHIC2 to regulate IL-27Rα expression in mouse and human CD8+ T cells. IL-27Rα expression is essential for the accumulation of Stub1 KO or Chic2 KO CD8+ T cells in tumors and tumor growth control. Together, these findings demonstrate that the STUB1-CHIC2 complex is a novel regulator of cytokine receptor expression in CD8+ T cells and provide the rationale for inhibiting this pathway to improve CD8+ T cell-mediated anti-tumor immunity.
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Project description:In vivo CRISPR screens in CD8+ T cells have previously uncovered targets for cancer immunotherapy, yet they have not been used to compare the key regulators important at different stages of CD8+ T cell activation. Here we present two 899-gene in vivo CRISPR screens using naive or activated CD8+ T cells to address this gap. These screens identified the E3 ubiquitin ligase STUB1 as a novel negative regulator of anti-tumor CD8+ T cells. Stub1 knockout (KO) CD8+ T cells control tumor growth across multiple murine models. Mechanistically, STUB1 interacts with the adapter protein CHIC2 to regulate cytokine receptor expression in mouse and human CD8+ T cells. Among the cytokine receptors regulated by this complex, IL-27Ra is essential for Stub1/Chic2 KO-mediated tumor growth control. Together, these findings establish that the STUB1-CHIC2 complex as a novel regulator of cytokine receptor expression in CD8+ T cells and provide rationale for inhibiting this pathway to enhance CD8+ T cell-mediated anti-tumor immunity.
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Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with
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2023-06-16 | MSV000092193 | MassIVE
Project description:The expansion, trafficking and functional effectiveness of adoptively transferred CD8+ T-cells play a critical role in mediating effective anti-tumor immunity. However, the mechanisms which program the highly proliferative and functional state of CD8+ T-cells are not completely understood. We hypothesized that IL-12, a cytokine commonly induced by TLR activation, could enhance T-cell priming by altering responsiveness to antigen and cytokines. Priming of tumor specific CD8+ T-cells in the presence of IL-12 induced the acquisition of a 'polyfunctional' effector response and increased the generation of memory cells. Moreover, IL-12 priming also promoted high levels of the IL-2 receptor alpha-chain (CD25) and robust IL-2 mediated activation of STAT5. This sensitivity to IL-2 translated into enhanced in vivo proliferation of adoptively transferred CD8+ T-cells. Furthermore, real-time, in vivo imaging of T-cell trafficking confirmed the ability of IL-12 priming to drive in vivo proliferation. IL-12 priming enhanced the anti-tumor function of adoptively transferred cells by reducing established subcutaneous tumor burden, and significantly increasing survival in an established intracranial tumor model. Finally, IL-12 priming of human PBMCs generates tumor specific T-cells phenotypically and functionally similar to IL-12 primed Pmel-1 T-cells. These results highlight IL-12 as an important mediator of CD8+ T-cell effector function and anti-tumor immunity. We primed Pmel-1 TCR transgenic CD8+ T-cells with cognate antigen and either IL-2 or IL-12 and compared their gene expression profiles. This was used to identify pathways or genes necessary for anti-tumor activity in vivo. RNA was isolated from Pmel-1 T-cells primed with antigen and cytokine for 6 days and hybridized to Affymetrix arrays.
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Project description:CD8 T cells are critical in combating cancer, but their effectiveness is hindered by exhaustion due to the immunosuppressive tumor microenvironment. Here, we examine the role of IL-3 in coordinating anti-tumor immunity resulting in increased CD8 T-cell functionality. IL-3 treatment of tumor-bearing mice increases CD8 T-cell effector function and protections against tumor progression. However, there is no evidence that IL-3 had direct effect on CD8 T cells. Instead, IL-3 exerts influences basophils to excrete IL-4, which is responsible for inducing increased IFN-γ production and viability of CD8 T cells. Taken together, these findings unveil an IL-3-mediated CD8 T cell-basophil crosstalk that regulates anti-tumor immunity, and offers a encouraging approach for augmenting cancer immunotherapy.
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Project description:The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about 36 regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFNγ-R1 cell surface abundance, we identified STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through IFNγ-R1K285 and JAK1K249. Conversely, STUB1 inactivation amplifies IFNγ signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This was corroborated by an anticorrelation between STUB1 expression and IFNγ response in ICB-treated patients. Consistent with the context-dependent effects of IFNγ in vivo, anti-PD-1 response was increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells but not full STUB1 knockout tumors. These results uncover STUB1 as a critical regulator of IFNγ-R1, and highlight the context-dependency of STUB1-regulated IFNγ signaling for ICB outcome.
2022-03-07 | PXD030580 | Pride