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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| Format: | Article |
| Language: | English |
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Wiley
2024-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202403438 |
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| author | Shenhui Yin Chunzhen Li Xin Shen Guanyu Yu Likun Cui Yunyang Wu Yixian He Shu Yu Jie Chen Shaoteng Lu Guifang Qiu Mengqi Song Cheng Qian Zui Zou Yizhi Yu Sheng Xu |
| author_facet | Shenhui Yin Chunzhen Li Xin Shen Guanyu Yu Likun Cui Yunyang Wu Yixian He Shu Yu Jie Chen Shaoteng Lu Guifang Qiu Mengqi Song Cheng Qian Zui Zou Yizhi Yu Sheng Xu |
| author_sort | Shenhui Yin |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-5f022f9e70da450fa1f49680c294eff2 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-5f022f9e70da450fa1f49680c294eff22025-08-20T02:19:01ZengWileyAdvanced Science2198-38442024-12-011145n/an/a10.1002/advs.202403438Siglec‐G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor ImmunotherapyShenhui Yin0Chunzhen Li1Xin Shen2Guanyu Yu3Likun Cui4Yunyang Wu5Yixian He6Shu Yu7Jie Chen8Shaoteng Lu9Guifang Qiu10Mengqi Song11Cheng Qian12Zui Zou13Yizhi Yu14Sheng Xu15National Key Laboratory of Immunity & Inflammation Naval Medical University/Second Military Medical University Shanghai 200433 ChinaNational Key Laboratory of Immunity & Inflammation Naval Medical University/Second Military Medical University Shanghai 200433 ChinaNational Key Laboratory of Immunity & Inflammation Naval Medical University/Second Military Medical University Shanghai 200433 ChinaDepartment of Colorectal Surgery Changhai Hospital Naval Medical University Shanghai 200433 ChinaNational Key Laboratory of Immunity & Inflammation Naval Medical University/Second Military Medical University Shanghai 200433 ChinaNational Key Laboratory of Immunity & Inflammation Naval Medical University/Second Military Medical University Shanghai 200433 ChinaNational Key Laboratory of Immunity & Inflammation Naval Medical University/Second Military Medical University Shanghai 200433 ChinaNational Key Laboratory of Immunity & Inflammation Naval Medical University/Second Military Medical University Shanghai 200433 ChinaNational Key Laboratory of Immunity & Inflammation Naval Medical University/Second Military Medical University Shanghai 200433 ChinaNational Key Laboratory of Immunity & Inflammation Naval Medical University/Second Military Medical University Shanghai 200433 ChinaNational Key Laboratory of Immunity & Inflammation Naval Medical University/Second Military Medical University Shanghai 200433 ChinaNational Key Laboratory of Immunity & Inflammation Naval Medical University/Second Military Medical University Shanghai 200433 ChinaNational Key Laboratory of Immunity & Inflammation Naval Medical University/Second Military Medical University Shanghai 200433 ChinaSchool of Anesthesiology Naval Medical University Shanghai 200433 ChinaNational Key Laboratory of Immunity & Inflammation Naval Medical University/Second Military Medical University Shanghai 200433 ChinaNational Key Laboratory of Immunity & Inflammation Naval Medical University/Second Military Medical University Shanghai 200433 ChinaAbstract 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.https://doi.org/10.1002/advs.202403438CD8+ T cellsmetabolic rewiringSiglec‐Gtumor immunotherapy |
| spellingShingle | Shenhui Yin Chunzhen Li Xin Shen Guanyu Yu Likun Cui Yunyang Wu Yixian He Shu Yu Jie Chen Shaoteng Lu Guifang Qiu Mengqi Song Cheng Qian Zui Zou Yizhi Yu Sheng Xu Siglec‐G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy Advanced Science CD8+ T cells metabolic rewiring Siglec‐G tumor immunotherapy |
| title | Siglec‐G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy |
| title_full | Siglec‐G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy |
| title_fullStr | Siglec‐G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy |
| title_full_unstemmed | Siglec‐G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy |
| title_short | Siglec‐G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy |
| title_sort | siglec g suppresses cd8 t cells responses through metabolic rewiring and can be targeted to enhance tumor immunotherapy |
| topic | CD8+ T cells metabolic rewiring Siglec‐G tumor immunotherapy |
| url | https://doi.org/10.1002/advs.202403438 |
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