Single-cell spatial transcriptomics unravels cell states and ecosystems associated with clinical response to immunotherapy
Background The tumor microenvironment (TME) is a complex and dynamic ecosystem that is known to influence responses to immunotherapy. We leveraged single-cell spatial transcriptomics to systematically dissect the intricate complexity of the TME, in particular the cellular heterogeneity and spatial i...
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BMJ Publishing Group
2025-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/3/e011308.full |
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| author | Sjoerd H van der Burg Ziena Abdulrahman Mariette I E van Poelgeest Roderick C Slieker Marij J P Welters Daniel McGuire |
| author_facet | Sjoerd H van der Burg Ziena Abdulrahman Mariette I E van Poelgeest Roderick C Slieker Marij J P Welters Daniel McGuire |
| author_sort | Sjoerd H van der Burg |
| collection | DOAJ |
| description | Background The tumor microenvironment (TME) is a complex and dynamic ecosystem that is known to influence responses to immunotherapy. We leveraged single-cell spatial transcriptomics to systematically dissect the intricate complexity of the TME, in particular the cellular heterogeneity and spatial interactions. Their collective impact on immunotherapy efficacy was studied in the context of a homogeneous group of patients with vulvar high-grade squamous intraepithelial lesions (vHSIL) treated with an immunotherapeutic tumor-specific peptide vaccine.Methods We performed single-cell spatial transcriptomics on 20 pretreatment vHSIL lesions, stratified by clinical response to immunotherapeutic vaccination into complete responders (CR), partial responders (PR) and non-responders (NR). Using a 1,000-gene panel, we mapped over 274,000 single cells in situ, identifying 18 cell clusters and 99 distinct non-epithelial cell states. Findings were validated against public single-cell transcriptomic data sets to assess their broader relevance across tumor types.Results Profound heterogeneity within the TME was detected across the response groups. CR lesions exhibited a higher ratio of immune-supportive to immune-suppressive cells—a pattern mirrored in other solid tumors following neoadjuvant checkpoint blockade. Key immune populations enriched in CRs included CD4+CD161+ effector T cells and chemotactic CD4+ and CD8+ T cells. Conversely, PRs were characterized by increased proportions of T helper 2 cells and CCL18-expressing macrophages, which are associated with the recruitment of type 2 T cells and regulatory T cells. NRs displayed preferential infiltration with immunosuppressive fibroblasts. Distinct spatial immune ecosystems further defined response groups. Although a number of immune cells were detected in all patients, type 1 effector cells dominated interactions in CRs, type 2 cells were prominently interacting in PRs, while NRs lacked organized immune cell interactions.Conclusions This study underscores the dual importance of both cellular composition and spatial organization in steering clinical response to immunotherapy. |
| format | Article |
| id | doaj-art-c40e628fae1e4e6093a04e8c0f7cd0fa |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-c40e628fae1e4e6093a04e8c0f7cd0fa2025-08-20T01:50:06ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-03-0113310.1136/jitc-2024-011308Single-cell spatial transcriptomics unravels cell states and ecosystems associated with clinical response to immunotherapySjoerd H van der Burg0Ziena Abdulrahman1Mariette I E van Poelgeest2Roderick C Slieker3Marij J P Welters4Daniel McGuire5Department of Medical Oncology, Leiden University Medical Center, Leiden, The NetherlandsMedical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Gynecology, Leiden University Medical Center, Leiden, The Netherlandspostdoctoral fellowOncode Institute, Utrecht, The Netherlands4 NanoString Technologies Inc, Seattle, Washington, USABackground The tumor microenvironment (TME) is a complex and dynamic ecosystem that is known to influence responses to immunotherapy. We leveraged single-cell spatial transcriptomics to systematically dissect the intricate complexity of the TME, in particular the cellular heterogeneity and spatial interactions. Their collective impact on immunotherapy efficacy was studied in the context of a homogeneous group of patients with vulvar high-grade squamous intraepithelial lesions (vHSIL) treated with an immunotherapeutic tumor-specific peptide vaccine.Methods We performed single-cell spatial transcriptomics on 20 pretreatment vHSIL lesions, stratified by clinical response to immunotherapeutic vaccination into complete responders (CR), partial responders (PR) and non-responders (NR). Using a 1,000-gene panel, we mapped over 274,000 single cells in situ, identifying 18 cell clusters and 99 distinct non-epithelial cell states. Findings were validated against public single-cell transcriptomic data sets to assess their broader relevance across tumor types.Results Profound heterogeneity within the TME was detected across the response groups. CR lesions exhibited a higher ratio of immune-supportive to immune-suppressive cells—a pattern mirrored in other solid tumors following neoadjuvant checkpoint blockade. Key immune populations enriched in CRs included CD4+CD161+ effector T cells and chemotactic CD4+ and CD8+ T cells. Conversely, PRs were characterized by increased proportions of T helper 2 cells and CCL18-expressing macrophages, which are associated with the recruitment of type 2 T cells and regulatory T cells. NRs displayed preferential infiltration with immunosuppressive fibroblasts. Distinct spatial immune ecosystems further defined response groups. Although a number of immune cells were detected in all patients, type 1 effector cells dominated interactions in CRs, type 2 cells were prominently interacting in PRs, while NRs lacked organized immune cell interactions.Conclusions This study underscores the dual importance of both cellular composition and spatial organization in steering clinical response to immunotherapy.https://jitc.bmj.com/content/13/3/e011308.full |
| spellingShingle | Sjoerd H van der Burg Ziena Abdulrahman Mariette I E van Poelgeest Roderick C Slieker Marij J P Welters Daniel McGuire Single-cell spatial transcriptomics unravels cell states and ecosystems associated with clinical response to immunotherapy Journal for ImmunoTherapy of Cancer |
| title | Single-cell spatial transcriptomics unravels cell states and ecosystems associated with clinical response to immunotherapy |
| title_full | Single-cell spatial transcriptomics unravels cell states and ecosystems associated with clinical response to immunotherapy |
| title_fullStr | Single-cell spatial transcriptomics unravels cell states and ecosystems associated with clinical response to immunotherapy |
| title_full_unstemmed | Single-cell spatial transcriptomics unravels cell states and ecosystems associated with clinical response to immunotherapy |
| title_short | Single-cell spatial transcriptomics unravels cell states and ecosystems associated with clinical response to immunotherapy |
| title_sort | single cell spatial transcriptomics unravels cell states and ecosystems associated with clinical response to immunotherapy |
| url | https://jitc.bmj.com/content/13/3/e011308.full |
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