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T helper 2 cell–directed immunotherapy eliminates precancerous skin lesions
Tomonori Oka, … , Lynn A. Cornelius, Shadmehr Demehri
Tomonori Oka, … , Lynn A. Cornelius, Shadmehr Demehri
Published January 2, 2025
Citation Information: J Clin Invest. 2025;135(1):e183274. https://doi.org/10.1172/JCI183274.
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Research Article Dermatology Oncology

T helper 2 cell–directed immunotherapy eliminates precancerous skin lesions

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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

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Figure 5

IL-24 is induced by Th2-associated cytokines in cancer cells, and its overexpression causes toxic autophagy in the cells.

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IL-24 is induced by Th2-associated cytokines in cancer cells, and its ov...
(A) Quantification of IL24 mRNA expression in SCC12 cells treated with IL-4 for 4 hours. Each dot represents a biological replicate (0, 20, 200 ng/mL: n = 6, 10 ng/mL: n = 4, Kruskal-Wallis test with Dunn’s multiple comparison test). (B) Quantification of IL24 mRNA expression in SCC12 cells treated with 20 ng/mL of IL-13 for 4 hours. Each dot represents a biological replicate (n = 4 in each group, Mann-Whitney U test). (C) Quantification of IL24 mRNA expression in SCC13 cells treated with 20 ng/mL of IL-4 for 4 hours. Each dot represents a biological replicate (n = 4 in each group, Mann-Whitney U test). (D and E) Quantification of IL24 mRNA expression in KERTr (D) and HaCaT (E) normal keratinocytes treated with 20 ng/mL of IL-4 for 4 hours. Each dot represents a biological replicate (n = 4 in each group, Mann-Whitney U test). (F–H) Representative flow cytometry histogram of annexin V and autophagic flux (F), and quantification of percentage cell death (G) and RFI of autophagic flux (H) in SCC12 cells infected with adenovirus vector overexpressing IL-24 (Ad.IL-24) and treated with 5-FU compared with control vector (Ad.null) and DMSO (n = 10 in each group, Mann-Whitney U test). (I–K) Representative flow cytometry histogram of annexin V and autophagic flux (I), and quantification of percentage cell death (J) and RFI of autophagic flux (K) in SCC12 cells infected with Ad.IL-24 and treated with 5-FU in the presence of 3MA compared with Ad.null (n = 6 in each group, Mann-Whitney U test). Bar graphs show mean + SD.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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