Dynamic single-cell mapping unveils Epstein‒Barr virus-imprinted T-cell exhaustion and on-treatment response
Open accessAbstract
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.
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High cost of single-cell multi-omics restricts measurement of large-scale cohorts, leading to data more often utilized for discovering new insights rather than for validation, which is commonly achieved by bulk RNA sequencing.
“The high cost of single-cell multi-omics restricts the measurement of large-scale cohorts, leading to data that is more often utilized for discovering new insights rather than for validation, which is commonly achieved by bulk RNA sequencing [25].”
From Single-cell sequencing to multi-omics: technologies and applications (2024) · cites this paper as [25]
The Results section, “Patient cohorts and study design” (page unavailable), describes a six-patient single-cell discovery cohort and validation in three larger cohorts using bulk RNA sequencing. The paper does not say that cost limited the single-cell cohort or establish that single-cell data are generally used more often for discovery than validation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEBV reduces ICI effectiveness through mechanisms such as increasing PD-L1 expression, linking to CD8+ T cell exhaustion, and recruiting immunosuppressive factors.
“These findings align with prior studies indicating that EBV reduces ICI effectiveness through mechanisms such as increasing PD-L1 expression, linking to CD8 + T cell exhaustion, and recruiting immunosuppressive factors110–113.”
From Microbiome meets immunotherapy: unlocking the hidden predictors of immune checkpoint inhibitors (2025) · cites this paper as [111]
The Results section on anti-LAG-3 blockade (page unavailable) links EBV-associated activation to a CD8+ T-cell exhaustion programme and reports persistent dysfunction after ICI treatment. It does not establish that EBV reduces ICI effectiveness by increasing PD-L1 expression or recruiting immunosuppressive factors; the Discussion also reports that an EBV-associated T-cell population predicted immunotherapy benefit. (LLM, conf=0.85)
Experimental — accuracy not yet measuredRe-emerged clonotypes in ISG-15+CD8+ T cells after treatment among EBV (+) patients were detected and associated with effector T population expressing CXCL13 in responsive EBV (+) tumor, indicating their significant importance in tumor immunochemotherapy response.
“Re-emerged clonotypes in ISG-15+CD8+ T cells after treatment among EBV (+) patients were detected and associated with effector T population expressing CXCL13 in responsive EBV (+) tumor, indicating their significant importance in tumor immunochemotherapy response.”
From Single-cell sequencing to multi-omics: technologies and applications (2024) · cites this paper as [25]
Instances such as measuring only TRA or TRB, or erroneous matching to more than two chains, do occur.
“Instances such as measuring only TRA or TRB, or erroneous matching to more than two chains, do occur [25].”
From Single-cell sequencing to multi-omics: technologies and applications (2024) · cites this paper as [25]
The Results section on the single-cell immune landscape reports T cells with at least one productive TCRα or β chain and others with more than one clonotype. It does not say that only TRA or TRB was measured, or that erroneous matches to more than two chains occurred. Searches for single-chain measurements and multiple-chain matching found no passage establishing those points; no page number was available in our copy. (LLM, conf=0.73)
Experimental — accuracy not yet measured
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Single-cell sequencing to multi-omics: technologies and applications
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“Notably, re-emerged clonotypes in ISG-15 + CD8 + T cells after treatment among EBV ( + ) patients were detected and associated with effector T population expressing CXCL13 in responsive EBV ( + ) tumor, indicating their significant importance in tumor immunoche-motherapy response [25].”
BackgroundInfluentialSelf-citationMicrobiome meets immunotherapy: unlocking the hidden predictors of immune checkpoint inhibitors
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- Authors
- Qiu, M.-Z., Wang, C., Wu, Z., Zhao, Q., Zhao, Z., Huang, C.-Y., Wu, W., Yang, L.-Q., Zhou, Z.-W., Zheng, Y., Pan, H.-M., Liu, Z., Zeng, Z.-L., Luo, H.-Y., Wang, F., Wang, F.-H., Yang, S.-Y., Huang, M.-X., Lian, Z., Zhang, H., & Xu, R.-H.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Sun Yat-sen University (CN)
- Guangdong Academy of Medical Sciences (CN)
- Sir Run Run Shaw Hospital (CN)
- University of Macau (MO)
- Corresponding author
- Zhang, Haiyan
- Xu, Rui-Hua
- ORCID
- Venue
- Signal Transduction and Targeted Therapy
- Published
- 2023-09-21
- Volume
- 8
- Issue
- 1
- Pages
- 370-370
- ISSN
- 2059-3635 (ISSN-L)
- PMC
- PMC10514267
- OpenAlex
- W4386932910
- Cited by
- 58
- References
- 42
- Citations by year
- 2026: 20 · 2025: 22 · 2024: 16
- FWCI
- 7.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (82173128, 82073377, 81772587, 82172861)
- Natural Science Foundation of Guangdong Province (2021A1515012439, 2021A1515011743)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- Epstein-Barr virus, EBV-associated gastric cancer, T cell exhaustion, CD8+ T cells, immunotherapy response prediction, LAG-3, CXCL13, tumor immune microenvironment, single-cell transcriptomics
- MeSH terms
- T-Cell Exhaustion, Herpesvirus 4, Human, Humans, Immunotherapy, CD8-Positive T-Lymphocytes, Epstein-Barr Virus Infections
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