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. Using cell transplantation and chemical-induced models of cSCC combined with inducible genetically engineered mouse models of psoriasis, we investigated how chronic skin and systemic inflammation affects squamous skin tumor initiation and progression. Here we show that in the context of severe psoriasis-like disease, neutrophil-dependent inflammation prevents squamous skin tumor development. Cellular and molecular analyses of psoriasis-like skin at the tumor 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 in keratinocytes. Furthermore, single-cell RNA sequencing demonstrated that inflammatory N1-like neutrophils mediate reprogramming of the cell-cell communication networks, while keratinocytes displayed diminished responsiveness to mitogenic signals, including epidermal growth factor and Wnt/β-catenin. Importantly, neutrophil depletion ameliorated psoriasis-like inflammation, abolished the senescence-like phenotype in keratinocytes and restored tumor growth. We propose that the release of neutrophil granules and NETs in psoriasis-like skin eliminate tumor cells and/or mediate oxidative and inflammatory stress-induced senescence in keratinocytes, thereby preventing tumor 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.
