title: Ubiquitin-like Molecule ISG15 Acts as an Immune Adjuvant to Enhance Antigen-specific CD8 T-cell Tumor Immunity.
abstract: ISG15 is an ubiquitin-like protein induced by type I interferon associated with antiviral activity. ISG15 is also secreted and known to function as an immunomodulatory molecule. However, ISG15's role in influencing the adaptive CD8 T-cell responses has not been studied. Here, we demonstrate the efficacy of ISG15 as a vaccine adjuvant, inducing human papilloma virus (HPV) E7-specific IFNγ responses as well as the percentage of polyfunctional, cytolytic, and effector CD8 T-cell responses. Vaccination with ISG15 conferred remarkable control and/or regression of established HPV-associated tumor-bearing mice. T-cell depletion coupled with adoptive transfer experiments revealed that ISG15 protective efficacy was CD8 T-cell mediated. Importantly, we demonstrate that ISG15 vaccine-induced responses could be generated independent of ISGylation, suggesting that responses were mostly influenced by free ISG15. Our results provide more insight into the immunomodulatory properties of ISG15 and its potential to serve as an effective immune adjuvant in a therapeutic tumor or infectious disease setting.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Villarreal
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Megan C
authors.initials: MC
authors.lastname: Wise
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Rebekah J
authors.initials: RJ
authors.lastname: Siefert
authors.affiliation: Inovio Pharmaceuticals, Inc., Plymouth Meeting, Pennsylvania, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center School of Pharmacy, Abilene, Texas, USA.
authors.forename: Laurence M
authors.initials: LM
authors.lastname: Wood
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Weiner
mesh_terms: D000276:Adjuvants, Immunologic; D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007114:Immunization; D008212:Lymphocyte Depletion; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D050725:Papillomavirus E7 Proteins / Q000276:immunology; D016415:Sequence Alignment; D014452:Ubiquitins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D019496:Cancer Vaccines; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D050725:Papillomavirus E7 Proteins; D014452:Ubiquitins; D019444:Vaccines, DNA; C059731:oncogene protein E7, Human papillomavirus type 16; C074034:ISG15 protein, human