083 Chemically-induced cutaneous neoplasms spontaneously regress in mice lacking autoimmune regulator

Abstract

Cutaneous squamous cell carcinomas (cSCCs) frequently arise from precancerous lesions known as actinic keratoses (AKs). Factors that determine whether an AK will progress to a cSCC, remain stable, or regress to normal tissue are poorly defined. In AK and cSCC mouse models upregulation of autoimmune regulator (Aire) is associated with skin inflammation and tumor onset and the genetic lack of Aire attenuates the early stages of skin tumorigenesis. Here, to better assess the role of Aire in the onset and promotion of AK- and cSCC-like lesions, we subjected germline Aire null mice (Aire-/-; FVB/NJ or C57BL/6J backgrounds) to a classic two-step chemical carcinogenesis protocol [1x 7,12-dimethylbenz[a]anthracene (DMBA), 2x/wk 12-O-Tetradecanoylphorbol-13-acetate (TPA)], which resulted in papilloma formation in 92% of all mice (n=36/39). Aire deficiency resulted in reduced papilloma burden and smaller sized papillomas compared to Aire+/+ control mice. Unexpectedly, we observed that all papillomas that formed in 12 out of 22 Aire-/- mice rapidly and synchronously regressed despite continued tumor promotion with TPA. Histopathology indicated that regressed papilloma tissue from Aire-/- mice more closely resembled normal mouse skin architecture than non-regressed papilloma tissue from Aire-/- mice or from Aire+/+ papilloma tissue. After 15 weeks of TPA treatment, CD8+ cells consistent with cytotoxic T cell infiltrate were observed in the stroma surrounding the hyperproliferative epithelium in non-regressed papilloma tissue from Aire-/- mice or Aire+/+ mice. However, these cells were markedly absent from regressed papilloma tissue in Aire-/- mice, suggesting that an absence of functional Aire may improve the anti-tumoral immune response during the early stages of skin tumorigenesis. Altogether, this study indicates that Aire contributes in multiple ways to the development of skin neoplasms (onset, promotion, and regression) and suggests that the targeting of Aire function may provide a therapeutic benefit to patients at risk for skin cancers.