title: Immunoprevention of chemical carcinogenesis through early recognition of oncogene mutations.
abstract: Prevention of tumors induced by environmental carcinogens has not been achieved. Skin tumors produced by polyaromatic hydrocarbons, such as 7,12-dimethylbenz(a)anthracene (DMBA), often harbor an H-ras point mutation, suggesting that it is a poor target for early immunosurveillance. The application of pyrosequencing and allele-specific PCR techniques established that mutations in the genome and expression of the Mut H-ras gene could be detected as early as 1 d after DMBA application. Further, DMBA sensitization raised Mut H-ras epitope-specific CTLs capable of eliminating Mut H-ras(+) preneoplastic skin cells, demonstrating that immunosurveillance is normally induced but may be ineffective owing to insufficient effector pool size and/or immunosuppression. To test whether selective pre-expansion of CD8 T cells with specificity for the single Mut H-ras epitope was sufficient for tumor prevention, MHC class I epitope-focused lentivector-infected dendritic cell- and DNA-based vaccines were designed to bias toward CTL rather than regulatory T cell induction. Mut H-ras, but not wild-type H-ras, epitope-focused vaccination generated specific CTLs and inhibited DMBA-induced tumor initiation, growth, and progression in preventative and therapeutic settings. Transferred Mut H-ras-specific effectors induced rapid tumor regression, overcoming established tumor suppression in tumor-bearing mice. These studies support further evaluation of oncogenic mutations for their potential to act as early tumor-specific, immunogenic epitopes in expanding relevant immunosurveillance effectors to block tumor formation, rather than treating established tumors.
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294;
authors.forename: Tahseen H
authors.initials: TH
authors.lastname: Nasti
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294;
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Rudemiller
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294;
authors.forename: J Barry
authors.initials: JB
authors.lastname: Cochran
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294; Skin Diseases Research Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294;
authors.forename: Hee Kyung
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294; Skin Diseases Research Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294;
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuruta
authors.affiliation: Division of Biostatistics, School of Public Health, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294; and.
authors.forename: Naomi S
authors.initials: NS
authors.lastname: Fineberg
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294; Skin Diseases Research Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294;
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294; Skin Diseases Research Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294; Birmingham, Alabama VA Medical Center, Birmingham, AL 35233 timares@uab.edu celmets@uab.edu.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Elmets
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294; Skin Diseases Research Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294; Birmingham, Alabama VA Medical Center, Birmingham, AL 35233 timares@uab.edu celmets@uab.edu.
authors.forename: Laura
authors.initials: L
authors.lastname: Timares
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D002273:Carcinogens / Q000633:toxicity; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004252:DNA Mutational Analysis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D011905:Genes, ras / Q000235:genetics* / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D017354:Point Mutation / Q000187:drug effects / Q000235:genetics*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D002273:Carcinogens; D016207:Cytokines; D000939:Epitopes; D015127:9,10-Dimethyl-1,2-benzanthracene