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A STUB1-CHIC2 complex decreases IL-27Rα expression on CD8+ T cells to restrain tumor immunity

GSE265929 Mus musculus Expression profiling by high throughput sequencing 7 samples Submitted 2025/06/10 Platform GPL19057
Summary
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.
Published in
A STUB1-CHIC2 complex inhibits CD8(+) T cells to restrain tumor immunity
LaFleur MW, Milling LE, Prathima P et al. · Nature immunology 2025 · PMID 40796662 · doi:10.1038/s41590-025-02231-6
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Also filed as BioProject PRJNA1104988 and SRA study SRP504323. Searching any of these in the dataset finder brings you back here.

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