Article Synopsis
- In vivo CRISPR screens have identified key targets for cancer immunotherapy in CD8 T cells, but many genome regions still need further exploration.
- Researchers studied 899 genes in CD8 T cells reacting to melanoma and found that the E3 ubiquitin ligase STUB1 negatively regulates anti-tumor CD8 T cell function.
- Knocking out Stub1 leads to better tumor control in mouse models by affecting cytokine receptor expression, especially interleukin-27 receptor α, suggesting that targeting the STUB1-CHIC2 pathway could boost anti-tumor immunity in CD8 T cells.
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Article Abstract
In vivo CRISPR screens in CD8 T cells have previously uncovered targets for cancer immunotherapy; however, a minority of the genome has been individually annotated, suggesting that additional regulators remain to be discovered. Here we assessed 899 genes in CD8 T cells responding to murine melanoma and identified the E3 ubiquitin ligase STUB1 as a new negative regulator of anti-tumor CD8 T cell function. We demonstrated that Stub1 knockout CD8 T cells effectively 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 regulated cytokine receptors, interleukin-27 receptor α is essential for tumor growth control mediated by Stub1/Chic2 knockout CD8 T cells. Together, these findings establish the STUB1-CHIC2 complex as a 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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| http://dx.doi.org/10.1038/s41590-025-02231-6 | DOI Listing |