title: Histone deacetylase inhibitor AR-42 enhances E7-specific CD8⁺ T cell-mediated antitumor immunity induced by therapeutic HPV DNA vaccination.
abstract: We have previously created a potent DNA vaccine encoding calreticulin linked to the human papillomavirus (HPV) oncogenic protein E7 (CRT/E7). While treatment with the CRT/E7 DNA vaccine generates significant tumor-specific immune responses in vaccinated mice, the potency with the DNA vaccine could potentially be improved by co-administration of a histone deacetylase inhibitor (HDACi) as HDACi has been shown to increase the expression of MHC class I and II molecules. Thus, we aimed to determine whether co-administration of a novel HDACi, AR-42, with therapeutic HPV DNA vaccines could improve the activation of HPV antigen-specific CD8(+) T cells, resulting in potent therapeutic antitumor effects. To do so, HPV-16 E7-expressing murine TC-1 tumor-bearing mice were treated orally with AR-42 and/or CRT/E7 DNA vaccine via gene gun. Mice were monitored for E7-specific CD8(+) T cell immune responses and antitumor effects. TC-1 tumor-bearing mice treated with AR-42 and CRT/E7 DNA vaccine experienced longer survival, decreased tumor growth, and enhanced E7-specific immune response compared to mice treated with AR-42 or CRT/E7 DNA vaccine alone. Additionally, treatment of TC-1 cells with AR-42 increased the surface expression of MHC class I molecules and increased the susceptibility of tumor cells to the cytotoxicity of E7-specific T cells. This study indicates the ability of AR-42 to significantly enhance the potency of the CRT/E7 DNA vaccine by improving tumor-specific immune responses and antitumor effects. Both AR-42 and CRT/E7 DNA vaccines have been used in independent clinical trials; the current study serves as foundation for future clinical trials combining both treatments in cervical cancer therapy.
  
  
  CONCLUSIONS
  AR-42, a novel HDAC inhibitor, enhances potency of therapeutic HPV DNA vaccines AR-42 treatment leads to strong E7-specific CD8+ T cell immune responses AR-42 improves tumor-specific immunity and antitumor effects elicited by HPV DNA vaccine AR-42 is more potent than clinically available HDACi in combination with HPV DNA vaccine.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Sung Yong
authors.initials: SY
authors.lastname: Lee
authors.forename: Zhuomin
authors.initials: Z
authors.lastname: Huang
authors.forename: Tae Heung
authors.initials: TH
authors.lastname: Kang
authors.forename: Ruey-Shyang
authors.initials: RS
authors.lastname: Soong
authors.forename: Jayne
authors.initials: J
authors.lastname: Knoff
authors.forename: Ellen
authors.initials: E
authors.lastname: Axenfeld
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology*; D053918:Papillomavirus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D014162:Transfection; D047368:Tumor Burden / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; D056572:Histone Deacetylase Inhibitors; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D019444:Vaccines, DNA; C059731:oncogene protein E7, Human papillomavirus type 16