T-bet+CD8+ T cells govern anti-PD-1 responses in microsatellite-stable gastric cancers
Abstract More than 90% of advanced gastric cancers (GC) are microsatellite-stable (MSS). Compared to the high response rate of immune checkpoint inhibitors (ICI) in microsatellite-instability-high (MSI-H) GCs, only 10% of unstratified MSS GCs respond to ICIs. In this study, we apply semi-supervised...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58958-1 |
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| author | Shiying Tang Xiaofang Che Jinyan Wang Ce Li Xin He Kezuo Hou Xiaojie Zhang Jia Guo Bowen Yang Danni Li Lili Cao Xiujuan Qu Zhenning Wang Yunpeng Liu |
| author_facet | Shiying Tang Xiaofang Che Jinyan Wang Ce Li Xin He Kezuo Hou Xiaojie Zhang Jia Guo Bowen Yang Danni Li Lili Cao Xiujuan Qu Zhenning Wang Yunpeng Liu |
| author_sort | Shiying Tang |
| collection | DOAJ |
| description | Abstract More than 90% of advanced gastric cancers (GC) are microsatellite-stable (MSS). Compared to the high response rate of immune checkpoint inhibitors (ICI) in microsatellite-instability-high (MSI-H) GCs, only 10% of unstratified MSS GCs respond to ICIs. In this study, we apply semi-supervised learning to stratify potential ICI responders in MSS GCs, achieving high accuracy, quantified by an area under the curve of 0.924. Spatial analysis of the tumor microenvironment of ICI-sensitive GCs reveals a high level of T-bet+ CD8 + T cell infiltration in their tumor compartments. T-bet+ CD8 + T cells exhibit superior anti-tumor activity due to their increased ability to infiltrate tumors and secrete cytotoxic molecules. Adoptive transfer of T-bet+ CD8 + T cells boosts anti-tumor immunity and confers susceptibility to ICIs in immune-ignorant MSS GCs in a humanized mouse model. Spatial RNA sequencing suggests a positive-feedback loop between T-bet+ T cells and PD-L1+ tumor cells, which eventually drives T cell exhaustion and can therefore be leveraged for ICI therapy. In summary, our research provides insights into the underlying mechanism of anti-tumor immunity and deepens our understanding of varied ICI responses in MSS GCs. |
| format | Article |
| id | doaj-art-90b2464efa534e29abdbc07efb9eea75 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-90b2464efa534e29abdbc07efb9eea752025-08-20T02:30:24ZengNature PortfolioNature Communications2041-17232025-04-0116111710.1038/s41467-025-58958-1T-bet+CD8+ T cells govern anti-PD-1 responses in microsatellite-stable gastric cancersShiying Tang0Xiaofang Che1Jinyan Wang2Ce Li3Xin He4Kezuo Hou5Xiaojie Zhang6Jia Guo7Bowen Yang8Danni Li9Lili Cao10Xiujuan Qu11Zhenning Wang12Yunpeng Liu13Department of Medical Oncology, The First Hospital of China Medical UniversityDepartment of Medical Oncology, The First Hospital of China Medical UniversityDepartment of Immunology, College of Basic Medical Sciences, China Medical UniversityDepartment of Medical Oncology, The First Hospital of China Medical UniversityDepartment of Medical Oncology, The First Hospital of China Medical UniversityDepartment of Medical Oncology, The First Hospital of China Medical UniversityDepartment of Medical Oncology, The First Hospital of China Medical UniversityDepartment of Medical Oncology, The First Hospital of China Medical UniversityDepartment of Medical Oncology, The First Hospital of China Medical UniversityDepartment of Medical Oncology, The First Hospital of China Medical UniversityDepartment of Medical Oncology, The First Hospital of China Medical UniversityDepartment of Medical Oncology, The First Hospital of China Medical UniversityDepartment of Surgical Oncology and General Surgery, The First Hospital of China Medical UniversityDepartment of Medical Oncology, The First Hospital of China Medical UniversityAbstract More than 90% of advanced gastric cancers (GC) are microsatellite-stable (MSS). Compared to the high response rate of immune checkpoint inhibitors (ICI) in microsatellite-instability-high (MSI-H) GCs, only 10% of unstratified MSS GCs respond to ICIs. In this study, we apply semi-supervised learning to stratify potential ICI responders in MSS GCs, achieving high accuracy, quantified by an area under the curve of 0.924. Spatial analysis of the tumor microenvironment of ICI-sensitive GCs reveals a high level of T-bet+ CD8 + T cell infiltration in their tumor compartments. T-bet+ CD8 + T cells exhibit superior anti-tumor activity due to their increased ability to infiltrate tumors and secrete cytotoxic molecules. Adoptive transfer of T-bet+ CD8 + T cells boosts anti-tumor immunity and confers susceptibility to ICIs in immune-ignorant MSS GCs in a humanized mouse model. Spatial RNA sequencing suggests a positive-feedback loop between T-bet+ T cells and PD-L1+ tumor cells, which eventually drives T cell exhaustion and can therefore be leveraged for ICI therapy. In summary, our research provides insights into the underlying mechanism of anti-tumor immunity and deepens our understanding of varied ICI responses in MSS GCs.https://doi.org/10.1038/s41467-025-58958-1 |
| spellingShingle | Shiying Tang Xiaofang Che Jinyan Wang Ce Li Xin He Kezuo Hou Xiaojie Zhang Jia Guo Bowen Yang Danni Li Lili Cao Xiujuan Qu Zhenning Wang Yunpeng Liu T-bet+CD8+ T cells govern anti-PD-1 responses in microsatellite-stable gastric cancers Nature Communications |
| title | T-bet+CD8+ T cells govern anti-PD-1 responses in microsatellite-stable gastric cancers |
| title_full | T-bet+CD8+ T cells govern anti-PD-1 responses in microsatellite-stable gastric cancers |
| title_fullStr | T-bet+CD8+ T cells govern anti-PD-1 responses in microsatellite-stable gastric cancers |
| title_full_unstemmed | T-bet+CD8+ T cells govern anti-PD-1 responses in microsatellite-stable gastric cancers |
| title_short | T-bet+CD8+ T cells govern anti-PD-1 responses in microsatellite-stable gastric cancers |
| title_sort | t bet cd8 t cells govern anti pd 1 responses in microsatellite stable gastric cancers |
| url | https://doi.org/10.1038/s41467-025-58958-1 |
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