Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
J Mol Med (Berl). 2013 Oct;91(10):1221-31. doi: 10.1007/s00109-013-1054-9. Epub 2013 May 29.
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.
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.
我们之前创建了一种有效的 DNA 疫苗，该疫苗编码与人类乳头瘤病毒（HPV）致癌蛋白 E7 相连的钙网蛋白（CRT/E7）。虽然 CRT/E7 DNA 疫苗治疗可在接种疫苗的小鼠中产生显著的肿瘤特异性免疫应答，但通过联合使用组蛋白去乙酰化酶抑制剂（HDACi），DNA 疫苗的效力可能会提高，因为 HDACi 已被证明可增加 MHC 类 I 和 II 分子的表达。因此，我们旨在确定与治疗性 HPV DNA 疫苗联合使用新型 HDACi AR-42 是否可以改善 HPV 抗原特异性 CD8+T 细胞的激活，从而产生有效的抗肿瘤作用。为此，用 AR-42 和/或 CRT/E7 DNA 疫苗通过基因枪对表达 HPV-16 E7 的 TC-1 荷瘤小鼠进行口服治疗。监测小鼠的 E7 特异性 CD8+T 细胞免疫应答和抗肿瘤作用。与单独用 AR-42 或 CRT/E7 DNA 疫苗治疗的小鼠相比，用 AR-42 和 CRT/E7 DNA 疫苗治疗的 TC-1 荷瘤小鼠的生存期更长，肿瘤生长减少，并且 E7 特异性免疫应答增强。此外，用 AR-42 处理 TC-1 细胞可增加 MHC 类 I 分子的表面表达，并增加肿瘤细胞对 E7 特异性 T 细胞细胞毒性的敏感性。这项研究表明，AR-42 通过改善肿瘤特异性免疫应答和抗肿瘤作用，可显著增强 CRT/E7 DNA 疫苗的效力。AR-42 和 CRT/E7 DNA 疫苗都已在独立的临床试验中使用；本研究为将来在宫颈癌治疗中联合使用这两种疗法的临床试验奠定了基础。
新型 HDAC 抑制剂 AR-42 增强了治疗性 HPV DNA 疫苗的效力 AR-42 治疗可引起强烈的 E7 特异性 CD8+T 细胞免疫应答 AR-42 改善 HPV DNA 疫苗引起的肿瘤特异性免疫和抗肿瘤作用 AR-42 与临床可用的 HDACi 联合使用时比单独使用 HPV DNA 疫苗更有效。
