Type 2 immunity to the rescue: enhancing antitumor immunity for skin cancer prevention

Cutaneous squamous cell carcinoma (cSCC) incidence and deaths continue to rise, underscoring the need for improved cSCC prevention. Elimination of actinic keratosis (AK) precursor lesions is a major strategy to prevent cSCC. Topical calcipotriol and 5-fluorouracil (5-FU) have been shown to eliminate AKs and reduce the risk of cSCC development, but the mechanism was undefined. In this issue of the JCI, Oka et al. demonstrate that type 2 immunity is necessary and sufficient for the elimination of premalignant keratinocytes and cSCC prevention. Paired biopsies from AK lesions and unaffected skin revealed that only keratinocytes from AKs produced thymic stromal lymphopoietin (TSLP) and damage-associated molecular patterns, resulting in selective recruitment of Th2 cells to the AK lesion. In mouse models of skin carcinogenesis, TSLP was necessary to recruit Th2 cells and trigger IL-24-mediated keratinocyte cell death. These findings suggest that the TSLP/Th2/IL-24 axis is a potential therapeutic target for SCC prevention.