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Siglec‐G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy
https://orcid.org/0009-0002-2216-6426
https://orcid.org/0000-0002-3793-1154
https://orcid.org/0000-0002-9547-8052
AbstractCD8+ 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.
Siglec‐G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy
https://orcid.org/0009-0002-2216-6426
https://orcid.org/0000-0002-3793-1154
https://orcid.org/0000-0002-9547-8052
AbstractCD8+ 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.
Siglec‐G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy
https://orcid.org/0009-0002-2216-6426
https://orcid.org/0000-0002-3793-1154
https://orcid.org/0000-0002-9547-8052
AbstractCD8+ 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.
Siglec‐G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy
Advanced Science
Yin, Shenhui (Autor:in) / Li, Chunzhen (Autor:in) / Shen, Xin (Autor:in) / Yu, Guanyu (Autor:in) / Cui, Likun (Autor:in) / Wu, Yunyang (Autor:in) / He, Yixian (Autor:in) / Yu, Shu (Autor:in) / Chen, Jie (Autor:in) / Lu, Shaoteng (Autor:in)
Advanced Science ; 11
01.12.2024
Aufsatz (Zeitschrift)
Elektronische Ressource
Englisch
| Wiley | 2024
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