Siglec‐G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy
Abstract CD8+ T cells play a critical role in cancer immune‐surveillance and pathogen elimination. However, their effector function can be severely impaired by inhibitory receptors such as programmed death‐1 (PD‐1) and T cell immunoglobulin domain and mucin domain‐3 (Tim‐3). Here Siglec‐G is identif...
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-12-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202403438 |
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| Summary: | Abstract CD8+ T cells play a critical role in cancer immune‐surveillance and pathogen elimination. However, their effector function can be severely impaired by inhibitory receptors such as programmed death‐1 (PD‐1) and T cell immunoglobulin domain and mucin domain‐3 (Tim‐3). Here Siglec‐G is identified as a coinhibitory receptor that limits CD8+ T cell function. Siglec‐G is highly expressed on tumor‐infiltrating T cells and is enriched in the exhausted T cell subset. Ablation of Siglec‐G enhances the efficacy of adoptively transferred T cells and chimeric antigen receptor (CAR) T cells in suppressing solid tumors growth. Mechanistically, sialoglycan ligands, such as CD24 on tumor cells, activate the Siglec‐G‐SHP2 axis in CD8+ T cells, impairing metabolic reprogramming from oxidative phosphorylation to glycolysis, which dampens cytotoxic T lymphocyte (CTL) activation, expansion, and cytotoxicity. These findings discover a critical role for Siglec‐G in inhibiting CD8+ T cell responses, suggesting its potential therapeutic effect in adoptive T cell therapy and tumor immunotherapy. |
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| ISSN: | 2198-3844 |