Single cell and spatial analysis of immune-hot and immune-cold tumours identifies fibroblast subtypes associated with distinct immunological niches and positive immunotherapy response
Abstract Cancer-associated Fibroblasts (CAFs) have emerged as critical regulators of anti-tumour immunity, with both beneficial and detrimental properties that remain poorly characterised. To investigate this, we performed single-cell and spatial transcriptomic analysis, comparing head & neck sq...
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| Format: | Article |
| Language: | English |
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BMC
2025-01-01
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| Series: | Molecular Cancer |
| Online Access: | https://doi.org/10.1186/s12943-024-02191-9 |
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| author | Benjamin H. Jenkins Ian Tracy Maria Fernanda S. D. Rodrigues Melanie J. L. Smith Begoña R. Martinez Mark Edmond Sangeetha Mahadevan Anjali Rao Hailing Zong Kai Liu Abhishek Aggarwal Li Li Lauri Diehl Emma V. King Jamie G. Bates Christopher J. Hanley Gareth J. Thomas |
| author_facet | Benjamin H. Jenkins Ian Tracy Maria Fernanda S. D. Rodrigues Melanie J. L. Smith Begoña R. Martinez Mark Edmond Sangeetha Mahadevan Anjali Rao Hailing Zong Kai Liu Abhishek Aggarwal Li Li Lauri Diehl Emma V. King Jamie G. Bates Christopher J. Hanley Gareth J. Thomas |
| author_sort | Benjamin H. Jenkins |
| collection | DOAJ |
| description | Abstract Cancer-associated Fibroblasts (CAFs) have emerged as critical regulators of anti-tumour immunity, with both beneficial and detrimental properties that remain poorly characterised. To investigate this, we performed single-cell and spatial transcriptomic analysis, comparing head & neck squamous cell carcinoma (HNSCC) subgroups, which although heterogenous, can be considered broadly immune-hot and immune-cold (human papillomavirus [HPV]+ve and HPV-ve tumours respectively). This identified six fibroblast subpopulations, including two with immunomodulatory gene expression profiles (IL-11 + inflammatory [i]CAF and CCL19 + fibroblastic reticular cell [FRC]-like). IL-11 + iCAF were spatially associated with inflammatory monocytes and regulated in vitro through synergistic activation of canonical NF-κB signalling by IL-1β and TNF-α. FRC-like were enriched in immune-hot HPV+ve tumours, associated with CD4 + T-cells and B-cells in tertiary lymphoid structures and regulated through non-canonical NF-κB signalling via lymphotoxin. Pan-cancer analysis revealed several ‘iCAF’ subgroups present in both normal and cancer tissues; IL11 + iCAF were found in cancers from the gastrointestinal (GI) tract and transcriptomically distinct from iCAFs previously described in pancreatic and breast cancers with greater inflammatory properties; FRC-like fibroblasts were present at low frequencies in all tumour types, and were associated with significantly better survival in patients receiving checkpoint immunotherapy. This work clarifies and expands current literature on immunomodulatory CAFs, highlighting links with important immunological niches. |
| format | Article |
| id | doaj-art-c0b33e01bc644b64b5065f3534490e78 |
| institution | Kabale University |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-c0b33e01bc644b64b5065f3534490e782025-01-12T12:10:26ZengBMCMolecular Cancer1476-45982025-01-0124112110.1186/s12943-024-02191-9Single cell and spatial analysis of immune-hot and immune-cold tumours identifies fibroblast subtypes associated with distinct immunological niches and positive immunotherapy responseBenjamin H. Jenkins0Ian Tracy1Maria Fernanda S. D. Rodrigues2Melanie J. L. Smith3Begoña R. Martinez4Mark Edmond5Sangeetha Mahadevan6Anjali Rao7Hailing Zong8Kai Liu9Abhishek Aggarwal10Li Li11Lauri Diehl12Emma V. King13Jamie G. Bates14Christopher J. Hanley15Gareth J. Thomas16School of Cancer Sciences, University of SouthamptonSchool of Cancer Sciences, University of SouthamptonSchool of Cancer Sciences, University of SouthamptonSchool of Cancer Sciences, University of SouthamptonSchool of Cancer Sciences, University of SouthamptonSchool of Cancer Sciences, University of SouthamptonGilead Sciences Inc.Gilead Sciences Inc.Gilead Sciences Inc.Gilead Sciences Inc.Gilead Sciences Inc.Gilead Sciences Inc.Gilead Sciences Inc.School of Cancer Sciences, University of SouthamptonGilead Sciences Inc.School of Cancer Sciences, University of SouthamptonSchool of Cancer Sciences, University of SouthamptonAbstract Cancer-associated Fibroblasts (CAFs) have emerged as critical regulators of anti-tumour immunity, with both beneficial and detrimental properties that remain poorly characterised. To investigate this, we performed single-cell and spatial transcriptomic analysis, comparing head & neck squamous cell carcinoma (HNSCC) subgroups, which although heterogenous, can be considered broadly immune-hot and immune-cold (human papillomavirus [HPV]+ve and HPV-ve tumours respectively). This identified six fibroblast subpopulations, including two with immunomodulatory gene expression profiles (IL-11 + inflammatory [i]CAF and CCL19 + fibroblastic reticular cell [FRC]-like). IL-11 + iCAF were spatially associated with inflammatory monocytes and regulated in vitro through synergistic activation of canonical NF-κB signalling by IL-1β and TNF-α. FRC-like were enriched in immune-hot HPV+ve tumours, associated with CD4 + T-cells and B-cells in tertiary lymphoid structures and regulated through non-canonical NF-κB signalling via lymphotoxin. Pan-cancer analysis revealed several ‘iCAF’ subgroups present in both normal and cancer tissues; IL11 + iCAF were found in cancers from the gastrointestinal (GI) tract and transcriptomically distinct from iCAFs previously described in pancreatic and breast cancers with greater inflammatory properties; FRC-like fibroblasts were present at low frequencies in all tumour types, and were associated with significantly better survival in patients receiving checkpoint immunotherapy. This work clarifies and expands current literature on immunomodulatory CAFs, highlighting links with important immunological niches.https://doi.org/10.1186/s12943-024-02191-9 |
| spellingShingle | Benjamin H. Jenkins Ian Tracy Maria Fernanda S. D. Rodrigues Melanie J. L. Smith Begoña R. Martinez Mark Edmond Sangeetha Mahadevan Anjali Rao Hailing Zong Kai Liu Abhishek Aggarwal Li Li Lauri Diehl Emma V. King Jamie G. Bates Christopher J. Hanley Gareth J. Thomas Single cell and spatial analysis of immune-hot and immune-cold tumours identifies fibroblast subtypes associated with distinct immunological niches and positive immunotherapy response Molecular Cancer |
| title | Single cell and spatial analysis of immune-hot and immune-cold tumours identifies fibroblast subtypes associated with distinct immunological niches and positive immunotherapy response |
| title_full | Single cell and spatial analysis of immune-hot and immune-cold tumours identifies fibroblast subtypes associated with distinct immunological niches and positive immunotherapy response |
| title_fullStr | Single cell and spatial analysis of immune-hot and immune-cold tumours identifies fibroblast subtypes associated with distinct immunological niches and positive immunotherapy response |
| title_full_unstemmed | Single cell and spatial analysis of immune-hot and immune-cold tumours identifies fibroblast subtypes associated with distinct immunological niches and positive immunotherapy response |
| title_short | Single cell and spatial analysis of immune-hot and immune-cold tumours identifies fibroblast subtypes associated with distinct immunological niches and positive immunotherapy response |
| title_sort | single cell and spatial analysis of immune hot and immune cold tumours identifies fibroblast subtypes associated with distinct immunological niches and positive immunotherapy response |
| url | https://doi.org/10.1186/s12943-024-02191-9 |
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