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 HPV oncogenic protein E7 (CRT/E7). While treatment of the CRT/E7 DNA vaccine generates significant tumor-specific immune responses in vaccinated mice, the potency of the DNA vaccine could potentially be improved by co-administration of a histone deacetylase inhibitor (HDACi) as HDACi have 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 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 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 vaccine have been used in independent clinical trials and the current study serves as foundation for future clinical trials combining both treatments in cervical cancer therapy.

Evasion of host immune defenses by human papillomavirus

“…Consequently, IRF1 responsive genes, including the ATP-binding cassette (ABC) peptide transporter associated with antigen processing 1 (TAP1), IFN-β, and CCL2, are significantly downregulated in HPV16 E7 expressing cells and mice (Georgopoulos et al, 2000; Um et al, 2002). Consistently, treatment of HPV-positive tumor cells with an HDAC inhibitor increased the surface expression of the major histocompatibility complex class I (MHC-I) molecules, enhancing the susceptibility of tumor cells to E7-specific CD8 + T cells (Lee et al, 2013). …”

Epigenetic Modulation with Histone Deacetylase Inhibitors in Combination with Immunotherapy

“…HDAC inhibition enhanced antitumor response induced by Her-2/neu DNA vaccine, leading to significant delays in tumor progression and extending the lifespan of these mice. Similarly, AR-42 improved potency of therapeutic human papillomavirus (HPV) DNA vaccines by activating HPV antigen-specific CD8+ T cells and increasing the cell surface expression of MHC class I molecules on tumor cells [69]. These works suggest that co-administration of HDAC inhibitors can overcome the obstacles confronting cancer vaccine therapy and boost its potency by augmenting tumor-specific immunity.…”

Current state in the development of candidate therapeutic HPV vaccines

“…Administration of agonist antibody of costimulatory receptor 4-1BB along with E6/E7 peptide vaccine resulted in high CD8+ versus regulatory T cells ratio, infiltration of E7-specific CD8+ T cells, and regression of TC-1 tumors [99]. Histone deacetylase inhibitor (HDACi) has been shown to increase MHC I and II molecule expression on the surface of TC-1 tumor cells, making them more susceptible to E7-specific T cells generated through therapeutic HPV DNA vaccination [100]. Furthermore, local administration of molecules that activates innate immune responses such as imiquimod or GMCSF have been shown to lead to secretion of proinflammatory cytokines in the tumor location, which promotes DCs maturation, migration, and cross presentation, resulting in potent local antigen-specific immune responses against TC-1 tumors [101,102].…”