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Authors
Supervisors
Dumoutier, Laure  
 ;
Baeck, Marie  
Abstract
(en) Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, and its incidence is steadily rising with increasing exposure to environmental carcinogens. In addition to genetic alterations, inflammatory processes contribute to cSCC development, particularly in settings of repeated epithelial damage. Interleukin 24 (IL 24), a member of the IL 20 cytokine subfamily, is implicated in several inflammatory skin diseases. In cancer, however, IL-24 is often regarded as tumor suppressive, and its role in cSCC remains unclear. The objective of this thesis was to define the role of IL-24 signaling in skin carcinogenesis. To address this, we used the DMBA/TPA two‑stage carcinogenesis model in Il24-deficient mice and mice lacking key IL-24 receptor chains (IL-20Rb and IL-22ra1). Unexpectedly, genetic ablation of Il24 delayed tumor onset and reduced tumor burden. A similar protection was observed when IL-24 receptor signaling was disrupted (Il20rb-/- or Il22ra1-/-). Despite this marked impact on tumor burden, IL‑24 and its receptors had limited effects on the global composition of the immune infiltrate and on classical IL‑24 target genes involved in apoptosis, angiogenesis or invasion. Instead, Il24 deficiency was associated with impaired induction of Il19 and of the alarmins S100a8, S100a9 and Il33, whose expression closely tracked tumor susceptibility across genotypes and was induced by IL‑24 in human keratinocytes. RNA-sequencing during early promotion captured IL 24 dependent transcriptional programs consistent with amplification of proliferative and inflammatory signatures. Finally, in a syngeneic transplantation model of established cSCC, host IL-24 signaling had minimal impact on tumor growth, supporting a predominant function of IL 24 during early expansion rather than late progression. Together, these data identify IL-24 signaling as a tumor-promoting pathway acting predominantly at early stages of chemical skin carcinogenesis, likely by reinforcing epithelial stress and alarmin expression (S100A8/A9, IL-33) in an inflammatory context. They further highlight the stage- and context-dependent nature of IL-24 functions in cancer.
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Choteau, M. (2026). Investigating the role of IL-24 in skin carcinogenesis. https://hdl.handle.net/2078.5/275692