Dynamic single-cell mapping unveils Epstein‒Barr virus-imprinted T-cell exhaustion and on-treatment response
Abstract Epstein‒Barr virus (EBV)-associated gastric cancer (GC) manifests an intriguing immunotherapy response. However, the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined. This study aimed to finely characterize the dynamic tumour immune contexture of...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-09-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-023-01622-1 |
| _version_ | 1827707997727490048 |
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| author | Miao-Zhen Qiu Chaoye Wang Zhiying Wu Qi Zhao Zhibin Zhao Chun-Yu Huang Wenwei Wu Li-Qiong Yang Zhi-Wei Zhou Yu Zheng Hong-Ming Pan Zexian Liu Zhao-Lei Zeng Hui-Yan Luo Feng Wang Feng-Hua Wang Si-Yu Yang Meng-Xing Huang Zhexiong Lian Haiyan Zhang Rui-Hua Xu |
| author_facet | Miao-Zhen Qiu Chaoye Wang Zhiying Wu Qi Zhao Zhibin Zhao Chun-Yu Huang Wenwei Wu Li-Qiong Yang Zhi-Wei Zhou Yu Zheng Hong-Ming Pan Zexian Liu Zhao-Lei Zeng Hui-Yan Luo Feng Wang Feng-Hua Wang Si-Yu Yang Meng-Xing Huang Zhexiong Lian Haiyan Zhang Rui-Hua Xu |
| author_sort | Miao-Zhen Qiu |
| collection | DOAJ |
| description | Abstract Epstein‒Barr virus (EBV)-associated gastric cancer (GC) manifests an intriguing immunotherapy response. However, the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined. This study aimed to finely characterize the dynamic tumour immune contexture of human EBV (+) GC treated with immunochemotherapy by longitudinal scRNA-seq and paired scTCR/BCR-seq. EBV (+) GC exhibits an inflamed-immune phenotype with increased T-cell and B-cell infiltration. Immunochemotherapy triggers clonal revival and reinvigoration of effector T cells which step to determine treatment response. Typically, an antigen-specific ISG-15+CD8+ T-cell population is highly enriched in EBV (+) GC patients, which represents a transitory exhaustion state. Importantly, baseline intratumoural ISG-15+CD8+ T cells predict immunotherapy responsiveness among GC patients. Re-emerged clonotypes of pre-existing ISG-15+CD8+ T cells could be found after treatment, which gives rise to a CXCL13-expressing effector population in responsive EBV (+) tumours. However, LAG-3 retention may render the ISG-15+CD8+ T cells into a terminal exhaustion state in non-responsive EBV (+) tumours. In accordance, anti-LAG-3 therapy could effectively reduce tumour burden in refractory EBV (+) GC patients. Our results delineate a distinct implication of EBV-imprinted on-treatment T-cell immunity in GC, which could be leveraged to optimize the rational design of precision immunotherapy. |
| first_indexed | 2024-03-10T16:57:29Z |
| format | Article |
| id | doaj.art-070815274a0c48edad394ffc82fe221e |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-03-10T16:57:29Z |
| publishDate | 2023-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-070815274a0c48edad394ffc82fe221e2023-11-20T11:04:26ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352023-09-018111310.1038/s41392-023-01622-1Dynamic single-cell mapping unveils Epstein‒Barr virus-imprinted T-cell exhaustion and on-treatment responseMiao-Zhen Qiu0Chaoye Wang1Zhiying Wu2Qi Zhao3Zhibin Zhao4Chun-Yu Huang5Wenwei Wu6Li-Qiong Yang7Zhi-Wei Zhou8Yu Zheng9Hong-Ming Pan10Zexian Liu11Zhao-Lei Zeng12Hui-Yan Luo13Feng Wang14Feng-Hua Wang15Si-Yu Yang16Meng-Xing Huang17Zhexiong Lian18Haiyan Zhang19Rui-Hua Xu20Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterMedical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityDepartment of Endoscopy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen UniversityDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterResearch Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical SciencesDepartment of Gastric Surgery, Sun Yat-sen University Cancer CenterDepartment of Internal Medical Oncology, Zhejiang University School of Medicine, Sir Run Run Shaw HospitalDepartment of Internal Medical Oncology, Zhejiang University School of Medicine, Sir Run Run Shaw HospitalResearch Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical SciencesResearch Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical SciencesDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterMedical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityMedical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityMedical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityCancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, China; MOE Frontier Science Centre for Precision Oncology, University of MacauDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterAbstract Epstein‒Barr virus (EBV)-associated gastric cancer (GC) manifests an intriguing immunotherapy response. However, the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined. This study aimed to finely characterize the dynamic tumour immune contexture of human EBV (+) GC treated with immunochemotherapy by longitudinal scRNA-seq and paired scTCR/BCR-seq. EBV (+) GC exhibits an inflamed-immune phenotype with increased T-cell and B-cell infiltration. Immunochemotherapy triggers clonal revival and reinvigoration of effector T cells which step to determine treatment response. Typically, an antigen-specific ISG-15+CD8+ T-cell population is highly enriched in EBV (+) GC patients, which represents a transitory exhaustion state. Importantly, baseline intratumoural ISG-15+CD8+ T cells predict immunotherapy responsiveness among GC patients. Re-emerged clonotypes of pre-existing ISG-15+CD8+ T cells could be found after treatment, which gives rise to a CXCL13-expressing effector population in responsive EBV (+) tumours. However, LAG-3 retention may render the ISG-15+CD8+ T cells into a terminal exhaustion state in non-responsive EBV (+) tumours. In accordance, anti-LAG-3 therapy could effectively reduce tumour burden in refractory EBV (+) GC patients. Our results delineate a distinct implication of EBV-imprinted on-treatment T-cell immunity in GC, which could be leveraged to optimize the rational design of precision immunotherapy.https://doi.org/10.1038/s41392-023-01622-1 |
| spellingShingle | Miao-Zhen Qiu Chaoye Wang Zhiying Wu Qi Zhao Zhibin Zhao Chun-Yu Huang Wenwei Wu Li-Qiong Yang Zhi-Wei Zhou Yu Zheng Hong-Ming Pan Zexian Liu Zhao-Lei Zeng Hui-Yan Luo Feng Wang Feng-Hua Wang Si-Yu Yang Meng-Xing Huang Zhexiong Lian Haiyan Zhang Rui-Hua Xu Dynamic single-cell mapping unveils Epstein‒Barr virus-imprinted T-cell exhaustion and on-treatment response Signal Transduction and Targeted Therapy |
| title | Dynamic single-cell mapping unveils Epstein‒Barr virus-imprinted T-cell exhaustion and on-treatment response |
| title_full | Dynamic single-cell mapping unveils Epstein‒Barr virus-imprinted T-cell exhaustion and on-treatment response |
| title_fullStr | Dynamic single-cell mapping unveils Epstein‒Barr virus-imprinted T-cell exhaustion and on-treatment response |
| title_full_unstemmed | Dynamic single-cell mapping unveils Epstein‒Barr virus-imprinted T-cell exhaustion and on-treatment response |
| title_short | Dynamic single-cell mapping unveils Epstein‒Barr virus-imprinted T-cell exhaustion and on-treatment response |
| title_sort | dynamic single cell mapping unveils epstein barr virus imprinted t cell exhaustion and on treatment response |
| url | https://doi.org/10.1038/s41392-023-01622-1 |
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