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 4

Calcipotriol-plus–5-FU treatment causes toxic autophagy and apoptosis associated with IL-24 induction in AK keratinocytes.

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Calcipotriol-plus–5-FU treatment causes toxic autophagy and apoptosis as...
(A) Representative images of cleaved caspase 7–stained AKs before (day 0) and after (day 7) calcipotriol-plus–5-FU treatment. (B) Quantification of cleaved caspase 7+ cells per total DAPI+ keratinocytes in AK before (day 0) and after (day 7) calcipotriol-plus–5-FU treatment. Each dot represents an AK sample (n = 18 participants at each time point, paired t test). (C) Representative images of cleaved caspase 3-stained AKs before (day 0) and after (day 7) calcipotriol-plus–5-FU treatment. (D) Quantification of cleaved caspase 3+ cells per total DAPI+ keratinocytes in AK before (day 0) and after (day 7) calcipotriol-plus–5-FU treatment. Each dot represents an AK sample (n = 18 participants at each time point, paired t test). (E) Representative images of LC3B-stained AKs before (day 0) and after (day 7) calcipotriol-plus–5-FU treatment. (F) Quantification of LC3B+ cells per total DAPI+ keratinocytes in AK before (day 0) and after (day 7) calcipotriol-plus–5-FU treatment. Each dot represents an AK sample (n = 18 participants at each time point, paired t test). (G) Volcano plot showing significantly upregulated (red dots) and downregulated (blue dots) genes in AKs collected from randomized clinical trial participants after calcipotriol-plus–5-FU treatment (day 5, n = 3) compared with before calcipotriol-plus–5-FU treatment (day 0, n = 3). Genes of interest are indicated with their symbol. (H) Representative images of IL-24–stained AKs before (day 0) and after (day 7) calcipotriol-plus–5-FU treatment. (I) Quantification of IL-24+ cells per total DAPI+ keratinocytes in AK before (day 0) and after (day 7) calcipotriol-plus–5-FU treatment. Each dot represents an AK sample (n = 18 participants at each time point, paired t test). (J) Representative images of IL-24–stained AKs treated with Vaseline-plus–5-FU versus calcipotriol-plus–5-FU (day 5). (K) Quantification of IL-24+ cells per total DAPI+ keratinocytes in AK treated with Vaseline-plus–5-FU (V + F) and calcipotriol-plus–5-FU (C and F). Each dot represents an AK sample (n = 20 participants for both treatment groups, Mann-Whitney U test). Bar graphs show mean + SD. Dashed lines mark the epidermal basement membrane in immunofluorescence images. Scale bars: 100 μm.