Psoriasis-like disease prevents squamous skin tumour development by neutrophil-driven inflammation 2251300

Abstract Introduction Psoriasis is a chronic inflammatory skin disease affecting millions of people worldwide. Although growing evidence links chronic inflammation with increased cancer risk, the association between psoriasis and cutaneous squamous cell carcinoma (cSCC) is still elusive. Methods Using cell transplantation and chemical-induced models of cSCC combined with genetic models of psoriasis, we investigated how chronic skin and systemic inflammation affects squamous skin tumour initiation and progression. Results Here we show that in the context of severe psoriasis-like disease, neutrophil-dependent inflammation prevents squamous skin tumour development. Cellular and molecular analyses of psoriasis-like skin at the tumour initiation stage revealed a marked infiltration of CD54—expressing neutrophils, associated with the release of cytotoxic granules and neutrophil extracellular traps (NETs), as well as enhanced senescence and the expression of senescence-associated secretory phenotype (SASP) in keratinocytes. Single-cell RNA sequencing combined with CellChat analysis demonstrated that in psoriasis-like skin, inflammatory N1-like neutrophils mediate re-programming of the cell-cell communication networks, while keratinocytes displayed diminished responsiveness to mitogenic and stem cell-niche signals, including EGF, LIF and WNT. Importantly, neutrophil depletion ameliorated psoriasis-like skin inflammation, abolished the senescence-like phenotype in keratinocytes and restored tumour growth. Conclusion We conclude that the release of neutrophil granules and NETs in psoriasis-like skin eliminate tumour cells and/or mediate oxidative and inflammatory stress-induced senescence in keratinocytes, thereby preventing tumour growth. Taken together, we have defined an innate control of skin tumorigenesis in psoriasis-like disease, which will be relevant for developing cancer prevention strategies. Funding Source H2020-MSCA and ERC Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)