Delayed Onset and Spontaneous Regression of DMBA/TPA-Induced Skin Lesions in Mice Lacking Autoimmune Regulator

Autoimmune regulator (AIRE) is a transcriptional regulator that directs tissue-specific antigen expression in medullary thymic epithelial cells ( Anderson and Su, 2016 Anderson M.S. Su M.A. AIRE expands: new roles in immune tolerance and beyond. Nat Rev Immunol. 2016; 16: 247-258 Crossref PubMed Scopus (146) Google Scholar ). AIRE expression also extends to extrathymic tissues, including the skin, testes, lymph nodes, tonsils, breast, and prostate ( Constantine and Lionakis, 2019 Constantine G.M. Lionakis M.S. Lessons from primary immunodeficiencies: autoimmune regulator and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Immunol Rev. 2019; 287: 103-120 Crossref PubMed Scopus (88) Google Scholar ). Several functional roles for extrathymic AIRE have been recently uncovered. In dendritic-like cells within lymph nodes, AIRE functions largely overlap with those in the thymus (e.g., gene transcription, chromatin remodeling) to regulate immunomodulation and immune tolerance in secondary lymphoid organs ( van Laar et al., 2022 van Laar G.G. van Hamburg J.P. Tas S.W. Extrathymic AIRE-expressing cells: friends or foes in autoimmunity and cancer?. Autoimmun Rev. 2022; 21: 103141 Crossref Scopus (2) Google Scholar ). Upregulated AIRE expression in cancer cell lines and mouse tumors (e.g., basal cell carcinoma, oral squamous cell carcinoma, or prostate cancer) has been correlated with increased expression of inflammatory cytokines/chemokines, oncogenic transcription factors, and markers of epithelial-to-mesenchymal transition ( Hobbs et al., 2015 Hobbs R.P. DePianto D.J. Jacob J.T. Han M.C. Chung B.M. Batazzi A.S. et al. Keratin-dependent regulation of Aire and gene expression in skin tumor keratinocytes. Nat Genet. 2015; 47: 933-938 Crossref PubMed Scopus (83) Google Scholar ; Kalra et al., 2018 Kalra R. Bhagyaraj E. Tiwari D. Nanduri R. Chacko A.P. Jain M. et al. AIRE promotes androgen-independent prostate cancer by directly regulating IL-6 and modulating tumor microenvironment. Oncogenesis. 2018; 7: 43 Crossref PubMed Scopus (16) Google Scholar ; Nguyen et al., 2020 Nguyen C.T.K. Sawangarun W. Mandasari M. Morita K.I. Harada H. Kayamori K. et al. AIRE is induced in oral squamous cell carcinoma and promotes cancer gene expression. PLoS One. 2020; 15e0222689 Google Scholar ). Conversely, high AIRE expression in breast cancer cells is associated with reduced markers of aggressiveness and is positively correlated with good prognosis for patients with estrogen receptor–positive breast cancer ( Bianchi et al., 2016 Bianchi F. Sommariva M. De Cecco L. Triulzi T. Romero-Cordoba S. Tagliabue E. et al. Expression and prognostic significance of the autoimmune regulator gene in breast cancer cells. Cell Cycle. 2016; 15: 3220-3229 Crossref PubMed Scopus (12) Google Scholar ). Thus, molecular functions for AIRE in nonthymic cells depend on cell type, tissue type, and biological context. Because AIRE expression is inducible in mouse models of carcinogenesis, we sought to determine how AIRE deficiency contributes to the early stages of cutaneous squamous cell carcinoma (cSCC) using a two-step chemical carcinogenesis paradigm in mice. All animal studies were approved by the Penn State College of Medicine Institutional Animal Care and Use Committee.