A STUB1-CHIC2 complex decreases IL-27Rα expression on CD8+ T cells to restrain tumor immunity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1104988 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28818100_1.fastq.gz | Fastqsanger.gz | |||
| SRR28818100_2.fastq.gz | Fastqsanger.gz | |||
| SRR28818101_1.fastq.gz | Fastqsanger.gz | |||
| SRR28818101_2.fastq.gz | Fastqsanger.gz | |||
| SRR28818102_1.fastq.gz | Fastqsanger.gz |
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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: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:A STUB1-CHIC2 complex decreases IL-27Rα expression on CD8+ T cells to restrain tumor immunity [RNAseq_STUB1KO]
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