An Investigation of the Spontaneous Regression of Chemically-Induced Neoplastic Skin Lesions in Mice Lacking Autoimmune Regulator
Restricted (Penn State Only)
- Author:
- Lesko, Elizabeth
- Graduate Program:
- Biomedical Sciences
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- June 28, 2023
- Committee Members:
- Ryan Hobbs, Thesis Advisor/Co-Advisor
Amanda Marie Nelson, Committee Member
Ralph Keil, Program Head/Chair
Lisa M Shantz, Thesis Advisor/Co-Advisor
Christopher Charles Norbury, Committee Member - Keywords:
- Autoimmune Regulator
Non-melanoma skin cancer
Squamous Cell Carcinoma
Mouse model
Cancer
Regression
Chemical carcinogenesis - Abstract:
- Cutaneous squamous cell carcinoma (cSCC) is a highly prevalent form of skin cancer for which there are limited treatment options. The mechanisms by which cSCC develops and resolves are still poorly understood, though the immune system plays a key role in both processes. We sought to determine the potential role of the protein Autoimmune Regulator (AIRE) in the development of cSCC given its known function in adaptive immunity and its transcriptional upregulation in skin under stress conditions. Using a two-step chemical carcinogenesis model of cSCC in mice, we compared the early development of neoplastic skin lesions in mice lacking AIRE globally to their AIRE-competent counterparts. We found that Aire-/- mice developed fewer, smaller lesions than Aire+/+ mice with a slight delay (about 1.5 weeks) in the first emergence of visible lesions in the mice lacking AIRE. The majority (66%) of Aire-/- mice also exhibited unexpected spontaneous regression of the neoplastic skin lesions after several weeks of treatment despite continued application of a tumor-promoting phorbol ester. Upon further characterization of the neoplastic lesions after up to 25 weeks of treatment, the regressing subpopulation of Aire-/- mice displayed reduced proliferation and increased CD8+ T cell infiltration in the epidermal regions of the neoplasms during the early stages of regression, followed by increased proliferation and reduced CD8+ T cell presence during late regression. Non-regressing Aire-/- mice demonstrated proliferation and CD8+ T cell infiltrate comparable to Aire+/+ mice, suggesting that these changes are due to the onset of regression rather than purely a genotype effect. Overall, our data indicate a novel role for AIRE in supporting tumorigenesis at multiple stages of early cSCC development and suggest AIRE as a potential target for the induction of regression in cSCC prior to lesion transformation into the more dangerous carcinoma.