O2 Innate immune dysregulation drives recessive dystrophic epidermolysis bullosa-associated squamous cell carcinoma

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ID: 318412
2026
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Abstract
Abstract Introduction and aims Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited, immunologically active, skin disorder, characterized by skin fragility and chronic inflammation, predisposing patients to aggressive early-onset squamous cell carcinoma (cSCC). Despite this, immunopathogenic mechanisms driving tumour progression remain poorly understood, while current treatments fail to address cancer initiation. This study aimed to characterize the RDEB-cSCC innate immune landscape to identify targetable pathways for therapeutic intervention. Methods We performed an integrated immune analysis using bulk RNA sequencing of matched nonlesional, perilesional and lesional biopsies as a strategy to model disease progression. This was complemented by peripheral blood immunophenotyping of healthy donors, patients with RDEB and patients with RDEB-cSCC to identify innate immune alterations associated with disease severity. To validate therapeutic targets, a patient-derived three-dimensional immunocompetent spheroid model was established, designed to recapitulate key tumour-promoting immune features, observed in patients with RDEB-cSCC. Results Transcriptomic profiling revealed a severity-dependent macrophage enrichment and activation of the immunoregulatory pathway, Janus kinase/signal transducer and activator of transcription (JAK/STAT)3, previously identified as a promising target in RDEB-cSCC. Lesional tissue and patient plasma exhibited concurrent upregulation of both pro- and anti-inflammatory cytokine signatures, indicating a dysregulated immune response. Peripheral immune profiling further revealed a significant shift towards alternatively activated monocytes, expressing CD163 and Tim4, suggesting a prepriming of precursor tumour-associated macrophages, linked to aggressive disease progression. Uniform manifold approximation and projection analysis identified unique monocyte clusters specific to RDEB-cSCC, associated with aggressive tumour behaviour. To functionally validate these tumour-promoting immune features, an immunocompetent spheroid model was developed recapitulating protumour macrophage differentiation and cytokines release associated with JAK/STAT3 activation. Targeting the model with the clinically approved JAK1/2 inhibitor, ruxolitinib, resulted in reduced spheroid growth, increase necrosis and a significant shift in monocyte polarization towards antitumour phenotype. Conclusions These findings highlight the innate immune dysregulation as a central driver of RDEB-cSCC, and targeting the monocyte–macrophage plasticity via the JAK/STAT3 pathway could be a potential early intervention strategy for treating RDEB-cSCC.
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Authors Madalina Alexandru, Imogen Brooks, Xinyi Chen, Veronika Morávková, Nadira Ali, John A McGrath, Jemima E. Mellerio, Sophia N. Karagiannis, Joanna Jackow-Malinowska
Journal the british journal of dermatology
Year 2026
DOI
10.1093/bjd/ljag151.002
URL
https://doi.org/10.1093/bjd/ljag151.002
Keywords Keywords not found

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