BACKGROUND. Actinic keratosis is a precursor to cutaneous squamous cell carcinoma. Long treatment durations and severe side effects have limited the efficacy of current actinic keratosis treatments. Thymic stromal lymphopoietin (TSLP) is an epithelium-derived cytokine that induces a robust antitumor immunity in barrier-defective skin. Here, we investigated the efficacy of calcipotriol, a topical TSLP inducer, in combination with 5-fluorouracil (5-FU) as an immunotherapy for actinic keratosis.
METHODS. The mechanism of calcipotriol action against skin carcinogenesis was examined in genetically engineered mouse models. The efficacy and safety of 0.005% calcipotriol ointment combined with 5% 5-FU cream were compared with Vaseline plus 5-FU for the field treatment of actinic keratosis in a randomized, double-blind clinical trial involving 131 participants. The assigned treatment was self-applied to the entirety of the qualified anatomical sites (face, scalp, and upper extremities) twice daily for 4 consecutive days. The percentage of reduction in the number of actinic keratoses (primary outcome), local skin reactions, and immune activation parameters were assessed.
RESULTS. Calcipotriol suppressed skin cancer development in mice in a TSLP-dependent manner. Four-day application of calcipotriol plus 5-FU versus Vaseline plus 5-FU led to an 87.8% versus 26.3% mean reduction in the number of actinic keratoses in participants (P < 0.0001). Importantly, calcipotriol plus 5-FU treatment induced TSLP, HLA class II, and natural killer cell group 2D (NKG2D) ligand expression in the lesional keratinocytes associated with a marked CD4+ T cell infiltration, which peaked on days 10–11 after treatment, without pain, crusting, or ulceration.
CONCLUSION. Our findings demonstrate the synergistic effects of calcipotriol and 5-FU treatment in optimally activating a CD4+ T cell–mediated immunity against actinic keratoses and, potentially, cancers of the skin and other organs.
FUNDING. Not applicable (investigator-initiated clinical trial).
Trevor J. Cunningham, Mary Tabacchi, Jean-Pierre Eliane, Sara Moradi Tuchayi, Sindhu Manivasagam, Hengameh Mirzaalian, Ahu Turkoz, Raphael Kopan, Andras Schaffer, Arturo P. Saavedra, Michael Wallendorf, Lynn A. Cornelius, Shadmehr Demehri
(A and B) WT (TSLPR+/–) and TSLPR–/– sex-matched littermates were treated with the standard DMBA-TPA skin carcinogenesis protocol. Animals received calcipotriol (80 nmol) or EtOH (carrier only) on the back skin 3 times per week during the 15-week TPA treatment period (n ≥ 19 for each group). **P < 0.01, by log-rank test (A) and *P < 0.05 versus the WT plus EtOH group, by Student’s t test (B). (C) Scheme used to investigate the role of transient TSLP induction by calcipotriol in skin cancer development. Age- and sex-matched WT mice were treated on their back skin with the standard DMBA-TPA protocol. At the first sign of tumor development (week 5), the animals were randomized into 2 groups and received calcipotriol (80 nmol) or EtOH in their ears for 3 consecutive days. Thereafter, the animals continued to receive TPA biweekly and were analyzed at 15 weeks (n ≥ 4 for each group). (D) Serum TSLP levels after 3 days of topical treatment with calcipotriol versus EtOH. *P < 0.05, by Student’s t test. (E) Number of tumors developed on each mouse after calcipotriol/EtOH treatment. *P < 0.05, by Student’s t test. (F) Representative pictures of the tumor-bearing mice and average weight of the 7 largest tumors in each group. Scale bar: 1 cm.