Single-cell spatial transcriptomics unravels cell states and ecosystems associated with clinical response to immunotherapy.

IF 10.3 1区 医学 Q1 IMMUNOLOGY Journal for Immunotherapy of Cancer Pub Date : 2025-03-13 DOI:10.1136/jitc-2024-011308
Ziena Abdulrahman, Roderick C Slieker, Daniel McGuire, Marij J P Welters, Mariette I E van Poelgeest, Sjoerd H van der Burg
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Abstract

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.

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单细胞空间转录组学揭示了与免疫疗法临床反应相关的细胞状态和生态系统。
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来源期刊
Journal for Immunotherapy of Cancer
Journal for Immunotherapy of Cancer Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
17.70
自引率
4.60%
发文量
522
审稿时长
18 weeks
期刊介绍: The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.
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