Histone deacetylase inhibitor AR-42 enhances E7-specific CD8+ T cell-mediated antitumor immunity induced by therapeutic HPV DNA vaccination

Sung Yong Lee, Zhuomin Huang, Tae Heung Kang, Ruey Shyang Soong, Jayne Knoff, Ellen Axenfeld, Chenguang Wang, Ronald D. Alvarez, Ching Shih Chen, Chien Fu Hung, T. C. Wu

Research output: Contribution to journalArticle

13 Citations (Scopus)

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. Key message: 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

Original languageEnglish
Pages (from-to)1221-1231
Number of pages11
JournalJournal of Molecular Medicine
Volume91
Issue number10
DOIs
Publication statusPublished - 2013 Oct 1

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DNA Vaccines
Histone Deacetylase Inhibitors
Cellular Immunity
Vaccination
T-Lymphocytes
DNA
Papillomavirus Vaccines
Therapeutics
Neoplasms
Papillomavirus E7 Proteins
Clinical Trials
Calreticulin
CD8 Antigens
Human papillomavirus 16
Firearms
Therapeutic Uses
Uterine Cervical Neoplasms
Immunity

Keywords

  • Cancer vaccine
  • Cervical cancer
  • Histone deacetylase inhibitor
  • Human papillomavirus

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Histone deacetylase inhibitor AR-42 enhances E7-specific CD8+ T cell-mediated antitumor immunity induced by therapeutic HPV DNA vaccination. / Lee, Sung Yong; Huang, Zhuomin; Kang, Tae Heung; Soong, Ruey Shyang; Knoff, Jayne; Axenfeld, Ellen; Wang, Chenguang; Alvarez, Ronald D.; Chen, Ching Shih; Hung, Chien Fu; Wu, T. C.

In: Journal of Molecular Medicine, Vol. 91, No. 10, 01.10.2013, p. 1221-1231.

Research output: Contribution to journalArticle

Lee, SY, Huang, Z, Kang, TH, Soong, RS, Knoff, J, Axenfeld, E, Wang, C, Alvarez, RD, Chen, CS, Hung, CF & Wu, TC 2013, 'Histone deacetylase inhibitor AR-42 enhances E7-specific CD8+ T cell-mediated antitumor immunity induced by therapeutic HPV DNA vaccination', Journal of Molecular Medicine, vol. 91, no. 10, pp. 1221-1231. https://doi.org/10.1007/s00109-013-1054-9
Lee, Sung Yong ; Huang, Zhuomin ; Kang, Tae Heung ; Soong, Ruey Shyang ; Knoff, Jayne ; Axenfeld, Ellen ; Wang, Chenguang ; Alvarez, Ronald D. ; Chen, Ching Shih ; Hung, Chien Fu ; Wu, T. C. / Histone deacetylase inhibitor AR-42 enhances E7-specific CD8+ T cell-mediated antitumor immunity induced by therapeutic HPV DNA vaccination. In: Journal of Molecular Medicine. 2013 ; Vol. 91, No. 10. pp. 1221-1231.
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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. Key message: 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",
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AU - Soong, Ruey Shyang

AU - Knoff, Jayne

AU - Axenfeld, Ellen

AU - Wang, Chenguang

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AB - 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. Key message: 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

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KW - Cervical cancer

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