A STUB1-CHIC2 complex decreases IL-27Rα expression on CD8+ T cells to restrain tumor immunity [RNAseq_STUB1KO]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1248550 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR33048745_1.fastq.gz | Fastqsanger.gz | |||
| SRR33048745_2.fastq.gz | Fastqsanger.gz | |||
| SRR33048749_1.fastq.gz | Fastqsanger.gz | |||
| SRR33048749_2.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: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.
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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 | 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:Zebrafish il-4 il-10 regulated immunity in gills
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Project description:Immune checkpoint blockade (ICB) leads to durable and complete tumour regression in some patients but in others gives temporary, partial or no response. Accordingly, significant efforts are underway to identify tumour-intrinsic mechanisms underlying ICB resistance. Results from a published CRISPR screen in a mouse model suggested that targeting STUB1, an E3 ligase involved in protein homeostasis, may overcome ICB resistance but the molecular basis of this effect remains unclear. Herein, we report an under-appreciated role of STUB1 to dampen the interferon gamma (IFNg) response. Genetic deletion of STUB1 increased IFNGR1 abundance on the cell surface and thus enhanced the downstream IFNg response as showed by multiple approaches including Western blotting, flow cytometry, qPCR, phospho-STAT1 assay, immunopeptidomics, proteomics, and gene expression profiling. Human prostate and breast cancer cells with STUB1 deletion were also susceptible to cytokine-induced growth inhibition. Furthermore, blockade of STUB1 protein function recapitulated the STUB1-null phenotypes. Despite these encouraging in vitro data and positive implications from clinical datasets, we did not observe in vivo benefits of inactivating Stub1 in mouse syngeneic tumour models - with or without combination with anti-PD-1 therapy. However, our findings elucidate STUB1 as a barrier to IFNg sensing, prompting further investigations to assess if broader inactivation of human STUB1 in both tumors and immune cells could overcome ICB resistance.
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