O5 Cancer-associated fibroblasts switch from immune-activating towards immune-suppressive function during cutaneous squamous cell carcinoma disease progression

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ID: 318418
2026
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Abstract
Abstract Introduction and aims Cancer-associated fibroblasts (CAFs) play an important role in the microenvironment of tumour growth. While cancer cells are well studied, the epigenetic and transcriptional evolution of CAFs from primary lesion, recurrence to metastasis in cutaneous squamous cell carcinoma (cSCC) disease remains unknown. Methods We developed a screening pipeline to profile primary CAFs and patient-matched control fibroblasts from different cSCC stages. Here, we established a unique isogenetic CAF series from a severe (T3) cSCC progressing from primary lesion, recurrence to metastasis formation and performed bulk RNA sequencing (RNAseq) and assay for transposase-accessible chromatin (ATAC)seq analysis. We further dissected their functional heterogeneity upon chemical manipulation of their chromatin state. Results Comparing 21 isolated CAFs with early and advanced cSCC (T1–T3) revealed that CAFs from higher-risk cSCC lose cell contractility and deposit more aligned extracellular matrix, potentially facilitating cancer cell invasion. Intriguingly, cell morphology analysis revealed that most features clustered CAFs based on their anatomical site of origin, whereas nuclear features clustered CAFs based on cSCC severity, suggesting a key role in disease progression. Integrated ATACseq and RNAseq of an isogenetic CAF progression series showed that CAFs cluster with disease progression as they start to express an epithelial–mesenchymal transition gene signature alongside progressive global chromatin compaction. During progression, CAFs shift from immune-activating and interferon-responsive programs toward stress-adapted, immune-suppressive states associated with activator protein (AP)-1 and nuclear factor (NF)-κB activity, resulting in distinct interferon-γ responses upon stimulation. These can be modulated by chromatin remodelling drugs and lead to distinct cancer cell CAF interactions three-dimensional organotypic cultures. Conclusions Comparing CAFs from different cSCC stages showed strong correlation of nuclear changes with cSCC severity. With disease progression CAF chromatin becomes globally more compact yet it selectively retains accessibility at loci associated with immune suppression and stress adaptation. Our data suggest that CAFs reinterpret inflammatory cues through regulatory programmes enriched for NF-κB and AP-1 activity, favouring immune-suppressive over immune-activating outputs.
Reference Key
openalex_W7165626160 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Tjaša Bensa, C. Harwood, Tanya Shaw, Emanuel Rognoni
Journal the british journal of dermatology
Year 2026
DOI
10.1093/bjd/ljag151.005
URL
https://doi.org/10.1093/bjd/ljag151.005
Keywords Keywords not found

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