Histone deacetylase inhibitor AR-42 enhances E7-specific CD8(+) T cell-mediated antitumor immunity induced by therapeutic HPV DNA vaccination
- Authors
- 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.
- Issue Date
- 10월-2013
- Publisher
- SPRINGER HEIDELBERG
- Keywords
- Cancer vaccine; Human papillomavirus; Cervical cancer; Histone deacetylase inhibitor
- Citation
- JOURNAL OF MOLECULAR MEDICINE-JMM, v.91, no.10, pp.1221 - 1231
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF MOLECULAR MEDICINE-JMM
- Volume
- 91
- Number
- 10
- Start Page
- 1221
- End Page
- 1231
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/102072
- DOI
- 10.1007/s00109-013-1054-9
- ISSN
- 0946-2716
- 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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