Skin cancer precursor immunotherapy for squamous cell carcinoma prevention
Abby R. Rosenberg, … , Lynn A. Cornelius, Shadmehr Demehri
Abby R. Rosenberg, … , Lynn A. Cornelius, Shadmehr Demehri
Published March 21, 2019
Citation Information: JCI Insight. 2019;4(6):e125476. https://doi.org/10.1172/jci.insight.125476.
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Clinical Research and Public Health Dermatology Oncology

Skin cancer precursor immunotherapy for squamous cell carcinoma prevention

Abstract

BACKGROUND. Topical calcipotriol plus 5-fluorouracil (5-FU) combination is an effective immunotherapy against actinic keratosis (AK), which is a precursor to squamous cell carcinoma (SCC). However, the long-term effectiveness of calcipotriol plus 5-FU treatment for SCC prevention is unknown. METHODS. We performed a blinded prospective cohort study on participants of a randomized double-blind clinical trial in which a 4-day course of topical calcipotriol plus 5-FU combination was compared to Vaseline plus 5-FU (control) for AK treatment. SCC and basal cell carcinoma (BCC) incidences were assessed at 1, 2, and 3 years after trial. Tissues were analyzed for calcipotriol plus 5-FU–induced T cell immunity in the skin. RESULTS. Calcipotriol plus 5-FU–induced tissue-resident memory T (Trm) cell formation in face and scalp skin associated with significantly higher erythema scores compared with control (P < 0.01). Importantly, more participants in the test cohort remained SCC-free over the more than 1,500-day follow-up period (P = 0.0765), and significantly fewer developed SCC on the treated face and scalp within 3 years (2 of 30 [7%] versus 11 of 40 [28%] in control group, hazard ratio 0.215 [95% CI: 0.048–0.972], P = 0.032). Accordingly, significantly more epidermal Trm cells persisted in the calcipotriol plus 5-FU–treated face and scalp skin compared with control (P = 0.0028). There was no significant difference in BCC incidence between the treatment groups. CONCLUSION. A short course of calcipotriol plus 5-FU treatment on the face and scalp is associated with induction of robust T cell immunity and Trm formation against AKs and significantly lowers the risk of SCC development within 3 years of treatment. FUNDING. This research was supported by internal academic funds and by grants from the Burroughs Wellcome Fund, Sidney Kimmel Foundation, Cancer Research Institute, and NIH.

Authors

Abby R. Rosenberg, Mary Tabacchi, Kenneth H. Ngo, Michael Wallendorf, Ilana S. Rosman, Lynn A. Cornelius, Shadmehr Demehri

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Figure 2

Immune activation, erythema, and Trm induction by calcipotriol plus 5-FU treatment.

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Immune activation, erythema, and Trm induction by calcipotriol plus 5-FU...
(A and B) The inflammation grades of AK biopsies are compared with the (A) erythema extent and (B) erythema intensity on the biopsied anatomical sites 1 day after completion of a 4-day treatment course. Note that the data include all participants in the prospective cohort study who contributed an AK biopsy during the clinical trial. P values were calculated by Fisher’s exact test. (C) Stacked bar chart compares the distribution of participants’ erythema extent in each treatment group for each treated anatomical site. **P < 0.001, ***P < 0.0001 by Fisher’s exact test. ns, not significant. (D) Stacked bar chart compares the distribution of participants’ erythema intensity in each treatment group for each treated anatomical site. *P < 0.01, **P < 0.001, ***P < 0.0001 by Fisher’s exact test. ns, not significant. (E) Representative histologic images show AKs that were biopsied on the face and scalp 1 day after treatment with calcipotriol plus 5-FU (C+F) or Vaseline plus 5-FU (V+F). Tissue samples were stained with H&E and with antibodies against CD3 plus CD4, CD69, or CD103 to detect induction of CD4+ T cell immunity and CD69+CD103+ Trm cells in the lesional skin. Erythema intensity associated with the site of the biopsies: face C+F, 3; face V+F, 0; scalp C+F, 2; scalp V+F, 1. Scale bars: 100 μm. (F) CD4+ T, CD8+ T, CD103+CD4+ Trm, and CD103+CD8+ Trm cells are quantified across 24 high-power field (hpf) images of 3 test (C+F) AKs and 20 hpf images of 3 control (V+F) AKs biopsied 1 day after treatment completion. **P < 0.001, ***P < 0.0001 by Wilcoxon’s rank-sum test.