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

Abstract

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.

Figure 1. Topical calcipotriol plus 5-FU stimulates immune surveillance in actinic keratosis and squamous cell carcinoma.

Sun-damaged skin harbors areas of normal epidermis mixed with areas of actinic keratosis, composed of transformed keratinocytes with dysregulated proliferation and differentiation, due to UV-induced somatic mutations. Topical calcipotriol induces TSLP production by transformed keratinocytes in actinic keratosis but not in unaffected keratinocytes. TSLP is recognized by T cells in the dermis and stimulates Th2 differentiation. Keratinocyte injury, mediated by the chemotherapeutic agent 5-FU, leads to expression of damage-associated molecular patterns including Annexin A1, Calreticulin, and MHC class II, which further promote T cell activation and proliferation. Activated Th2 cells secrete IL-4 and IL-13, which specifically stimulate transformed keratinocytes to express IL-24. IL-24 acts in an autocrine and paracrine fashion on transformed keratinocytes to enhance apoptosis, autophagy, and general cell death. In addition, ongoing stimulation of dermal T cells facilitates development of resident memory T cells (TRM) in the skin, allowing for long-term immunosurveillance and elimination of squamous cell carcinoma and its precursors.