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Citation Information: J Clin Invest. 2025;135(1):e183274. https://doi.org/10.1172/JCI183274.
Abstract
The continuous rise in skin cancer incidence highlights an imperative for improved skin cancer prevention. Topical calcipotriol-plus–5-fluorouracil (calcipotriol-plus–5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However, its mechanism of action remains unclear. Herein, we demonstrate that calcipotriol-plus–5-FU immunotherapy induces T helper type 2 (Th2) immunity, eliminating premalignant keratinocytes in humans. CD4+ Th2 cells were required and were sufficient downstream of thymic stromal lymphopoietin cytokine induction by calcipotriol to suppress skin cancer development. Th2-associated cytokines induced IL-24 expression in cancer cells, resulting in toxic autophagy and anoikis followed by apoptosis. Calcipotriol-plus–5-FU immunotherapy was dependent on IL-24 to suppress skin carcinogenesis in vivo. Collectively, our findings establish a critical role for Th2 immunity in cancer immunoprevention and highlight the Th2/IL-24 axis as an innovative target for skin cancer prevention and therapy.
Authors
Tomonori Oka, Sabrina S. Smith, Heehwa G. Son, Truelian Lee, Valeria S. Oliver-Garcia, Mahsa Mortaja, Kathryn E. Trerice, Lily S. Isakoff, Danielle N. Conrad, Marjan Azin, Neel S. Raval, Mary Tabacchi, Luni Emdad, Swadesh K. Das, Paul B. Fisher, Lynn A. Cornelius, Shadmehr Demehri
TSLP-the initiator or the terminator of inflammation?
Submitter: Krishna Ganti | krishna.set@mriu.edu.in
Authors: Krishna Ganti
Manav Rachna Internaitonal Institute of Research and Studies, Faridabad, India
Published February 25, 2025
The authors conclude that the Th2 immunity induced by the keratinocyte-derived TSLP is instrumental in eliminating the precancerous lesions and also protects skin from cancer development. The authors have used DMBA/TPA carcinogenesis mouse model [Figure 3A] to demonstrate the efficacy of calcipotriol plus 5-FU in skin cancer suppression. While the authors have shown that calcipotriol treatment induces TSLP gene expression in mouse skin [Figure 3E], the lacuna of assessment of the TSLP expression upon TPA treatment of mouse skin is striking. Notably, our earlier study has revealed that TPA treatment of mouse skin induces keratinocytic TSLP trancription as early as six hours post topical application. We have also demonstrated that the induction of TSLP transcription upon TPA treatment is mediated by the recruitment of AP1/NF-kB/STAT to their respective DNA binding sequences on the TSLP promoter.
Conflict of interests statement
The author has declared that no conflicts of interest exists.
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)