T helper 2 cell-directed immunotherapy eliminates precancerous skin lesions

• Published in: The Journal of clinical investigation 2025-01, Vol.135 (1)
• Main Authors: Oka, Tomonori, Smith, Sabrina S, Son, Heehwa G, Lee, Truelian, Oliver-Garcia, Valeria S, Mortaja, Mahsa, Trerice, Kathryn E, Isakoff, Lily S, Conrad, Danielle N, Azin, Marjan, Raval, Neel S, Tabacchi, Mary, Emdad, Luni, Das, Swadesh K, Fisher, Paul B, Cornelius, Lynn A, Demehri, Shadmehr
• Format: Article
• Language: English
• Subjects: Animals; Calcitriol - administration & dosage; Calcitriol - analogs & derivatives; Calcitriol - pharmacology; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - therapy; Cytokines - immunology; Cytokines - metabolism; Fluorouracil - administration & dosage; Fluorouracil - therapeutic use; Humans; Immunotherapy; Interleukins - genetics; Interleukins - immunology; Keratinocytes - immunology; Keratinocytes - pathology; Mice; Precancerous Conditions - immunology; Precancerous Conditions - pathology; Precancerous Conditions - prevention & control; Precancerous Conditions - therapy; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Skin Neoplasms - therapy; Th2 Cells - immunology
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI183274

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.