T helper 2 cell–directed immunotherapy eliminates precancerous skin lesions
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
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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Research Article Dermatology Oncology

T helper 2 cell–directed immunotherapy eliminates precancerous skin lesions

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 2

T cell immunity induced by calcipotriol-plus–5-FU immunotherapy persists over 5 years.

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T cell immunity induced by calcipotriol-plus–5-FU immunotherapy persists...
(A) Time from Vaseline-plus–5-FU versus calcipotriol-plus–5-FU treatment to biopsy for each participant in the follow-up clinical study. (B) Representative images of CD4/CD3-stained AKs from participants who had a history of (H/o) Vaseline-plus–5-FU versus calcipotriol-plus–5-FU treatment. (C and D) Quantification of CD3+ T cells (C) and CD4+ T cells (D) in AKs from participants who had a history of Vaseline-plus–5-FU versus calcipotriol-plus–5-FU treatment. Each dot represents cell counts from a high power field (hpf) image. 3 hpf images are included per sample (n = 5 participants in Vaseline-plus–5-FU group, n = 11 participants in calcipotriol-plus–5-FU group, Mann-Whitney U test). (E) Representative images of CD4/CD103-stained AKs from participants who had a history of Vaseline-plus–5-FU versus calcipotriol-plus–5-FU treatment. (F and G) Quantification of CD103+CD3+ T cells (F) and CD103+CD4+ T cells (G) in AKs from participants who had a history of Vaseline-plus–5-FU versus calcipotriol-plus–5-FU treatment. Each dot represents cell counts from an hpf image. 3 hpf images are included per sample (n = 5 participants in Vaseline-plus–5-FU group, n = 11 participants in calcipotriol-plus–5-FU group, Mann-Whitney U test). (H) Representative images of CD4/GATA3-stained AKs from participants who had a history of Vaseline-plus–5-FU versus calcipotriol-plus–5-FU treatment. (I) Quantification of GATA3+CD4+ T cells in AKs from participants who had a history of Vaseline-plus–5-FU versus calcipotriol-plus–5-FU treatment. Each dot represents cell counts from an hpf image. 3 hpf images are included per sample (n = 5 participants in Vaseline-plus–5-FU group, n = 11 participants in calcipotriol-plus–5-FU group, Mann-Whitney U test). (J) Representative images of ANXA1-stained AKs and normal skin. (K) Quantification of ANXA1+ cells in the epidermis of AKs and normal skin. (n = 16 participants for AK and normal skin samples, paired t test). (L) Representative images of HLA-II-stained AKs and normal skin. (M) Quantification of HLA-II+ cells in AKs and normal skin. (n = 16 participants for AK and normal skin samples, paired t test). (N) Schematic diagram depicting the mechanism by which calcipotriol-plus–5-FU immunotherapy induces Th2 immunity against AKs. Bar graphs show mean + SD. Dashed lines mark the epidermal basement membrane in immunofluorescence images. Scale bars: 100 μm.