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Principal Investigator: Craig A Elmets
Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Fiscal Year: 2023
Award: $185,625
Funding agency: National Institute of Environmental Health Sciences
ABSTRACT
Sunlight is the major environmental agent to which humans are exposed. Although it has beneficial effects (e.g.
metabolism of vitamin D, energy necessary for life), chronic overexposure to the ultraviolet portion causes DNA
damage, premature aging of the skin, immunosuppression and non-melanoma skin cancers (NMSCs) (i.e.
cutaneous squamous cell and basal cell carcinomas). In the U.S. alone >5 million new NMSCs are treated each
year. Though mortality from these malignancies is low, the overall socioeconomic burden exceeds $8 billion
annually. Because of the clinical significance of the problem, there has been intense interest in identifying
mechanisms by which UV radiation exerts its biologic effects and methods to prevent its adverse health effects.
UV-induced skin cancers are highly immunogenic. In addition, approximately 90% of human SCCs and 50% of
BCCs have mutations in the p53 tumor suppressor gene. The relationship between the immunogenicity of UV-
induced skin cancers and mutations in p53 is an unexplored area of investigation. This provides the rationale
for vaccinating against p53 mutations to evaluate its capacity to prevent the adverse effects of UV radiation. We
hypothesize that immunization against mutant p53 will result in the generation of CD8+ T-cells that preferentially
produce IFN-γ, which greatly reduce the mutations to which the immune response was generated, and, in turn,
reduce the carcinogenic effects of this form of radiant energy. We will examine this issue by first identifying
immunogenic mutant epitopes of p53 by assessing their ability in vitro and in vivo to stimulate T-cell-derived
cytokines and a cell-mediated immune response in mice. The immunization procedure will be evaluated in
vaccination mice for its efficacy in preventing UV-induced p53 mutations to which the immune response is
directed and in reducing the incidence of UV-induced tumors caused by those mutations. The ultimate goal of
these studies will be to assess whether UV-induced tumors can be prevented by mutant p53 vaccination.
Terms: <Actinic Rays><Adverse effects><Alleles><Allelomorphs><Anthracenes><Anti-Oncogenes><Antigenic Determinants><Antigens><Antineoplastic Vaccine><Antioncogene Protein p53><Antioncogenes><Approaches to prevention><Area><Aromatic Polycyclic Hydrocarbons><Basal Cell><Basal Cell Epithelioma><Basal cell carcinoma><Basiloma><Binding Determinants><Biological><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Cause><Cancer Etiology><Cancer Genes><Cancer Suppressor Genes><Cancer Vaccines><Cancer-Promoting Gene><Cancers><Cellular Tumor Antigen P53><Chronic><Clinical><Country><Cutaneous><Cutaneous Squamous Cell Carcinoma><DMBA><DNA Damage><DNA Injury><Development><Economic Burden><Emerogenes><Epidermoid Carcinoma><Epidermoid Skin Carcinoma><Epitopes><Exposure to><Exposure to ultraviolet radiation><Future><Generations><Genetic Alteration><Genetic Change><Genetic defect><Goals><Growth and Development><Growth and Development function><Health><Health Care Professional><Health Professional><Healthcare professional><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune><Immune Interferon><Immune Surveillance><Immune response><Immunes><Immunity><Immunization><Immunize><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunological response><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunosurveillance><In Vitro><Incidence><Induced DNA Alteration><Induced Mutation><Induced Sequence Alteration><Interferon Gamma><Interferon Type II><Investigation><Life><Malignant Neoplasms><Malignant Skin Neoplasm><Malignant Tumor><Measures><Messenger RNA><Methods><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Mutation><Neoplasm Vaccines><Non-Melanoma Skin Cancer><Onco-Suppressor Genes><Oncogenes><Oncogenes-Tumor Suppressors><Oncogenesis><Oncoprotein p53><P53><Peptides><Phosphoprotein P53><Phosphoprotein pp53><Planocellular Carcinoma><Premature Aging><Premature aging syndrome><Prevent skin cancer><Prevention><Prevention approach><Procedures><Protein TP53><Protocol><Protocols documentation><Radiation induced damage><Recessive Oncogenes><Recommendation><Rodent Ulcer><Skin><Skin Aging><Skin Cancer><Skin Carcinoma><Skin Neoplasms><Skin Tumor><Squamous Carcinoma><Squamous Cell><Squamous Cell Epithelioma><Squamous cell carcinoma><Sunblock><Sunlight><Sunscreening Agents><Sunscreens><System><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TP53><TP53 gene><TRP53><Techniques><Testing><Transforming Genes><Tumor Protein p53><Tumor Protein p53 Gene><Tumor Suppressing Genes><Tumor Suppressor Genes><Tumor Vaccines><UV Radiation Exposure><UV exposure><UV induced><UV irradiated><UV irradiation><UV irridated><UV light><UV radiation><UV radiation-induced><UV rays><Ultraviolet Radiation Related Exposure><Ultraviolet Rays><Ultraviolet radiation exposure><VIT D><Vaccinated><Vaccination><Vaccines><Vitamin D><aged skin><anti-tumor effect><anti-tumor vaccine><antigen-specific T cells><antitumor effect><antitumor vaccine><biologic><carcinogenicity><cell mediated immune response><clinical significance><clinically significant><cutaneous damage><cytokine><dermal damage><developmental><dimethylbenz(a)anthracene><dimethylbenzanthracene><environmental agent><experiment><experimental research><experimental study><experiments><exposed human population><genome mutation><hazard><host response><human exposure><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunogen><immunogenic><immunogenicity><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in vivo><interest><lFN-Gamma><mRNA><malignancy><malignant skin tumor><mortality><mouse development><mouse model><murine model><mutant><neoplasm/cancer><nonmelanoma skin cancer><oncosuppressor gene><p53 Antigen><p53 Genes><p53 Tumor Suppressor><peptide immunization><peptide vaccination><photoprotection><photoprotective><polyaromatic hydrocarbons><polynuclear aromatic hydrocarbon><prevent><preventing><protein p53><radiation damage><skin cancer prevention><skin damage><skin photoaging><skin solar aging><skin squamous cell carcinoma><socio-economic><socio-economically><socioeconomically><socioeconomics><sun block><sun damage><sun light><sun screen><sun tan booth><tanning bed><tanning booths><thymus derived lymphocyte><tumor><tumorigenesis><ultra violet><ultra violet irradiation><ultra violet light><ultra violet radiation><ultra violet rays><ultraviolet><ultraviolet exposure><ultraviolet induced><ultraviolet irradiation><ultraviolet light><ultraviolet light induced><ultraviolet radiation><ultraviolet radiation-induced><vaccine for cancer><vitamin metabolism>