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 immune-hot and immune-cold HNSCC subgroups (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 HPV+ve tumours, associated with CD4 T-cells and B-cells in tertiary lymphoid structures and regulated through non-canonical NF-kB 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 tract and transcriptomically distinct from iCAFs previously described in pancreatic and breast cancers with greater inflammatory properties; FRC-like fibroblasts, a rare phenotype but present in all tumour types, were associated with significantly better survival in patients receiving checkpoint immunotherapy. This work clarifies and expands current literature on immunomodulatory

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Identifiers

ORCID for Benjamin H. Jenkins: orcid.org/0000-0002-7588-0044

ORCID for Ian Tracy: orcid.org/0000-0003-4624-672X

ORCID for Melanie J.L. Smith: orcid.org/0009-0004-2631-9711

ORCID for Christopher J. Hanley: orcid.org/0000-0003-3816-7220

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