Abstract:Objective To investigate the effect of combination of histone deacetylase inhibitor (HDACI) Suberoylanilide Hydroxamic Acid (SAHA) combined with human papilloma virus 16 E7-DNA (HPV16E7-DNA) vaccine in the treatment of cervical cancer and its immunological mechanism. Methods The model of mice with TC-1 cervical cancer was made, then on the 5th day after tumor bearing, the mice were randomly divided into HPV16E7-DNA group, SAHA group, SAHA and HPV16E7-DNA group, control group by random number table method. The therapeutic regimen was as followed: HPV16E7-DNA group was given vaccine 5 μg/kg, SAHA group was given SAHA 20 mg/kg, SAHA and HPV16E7-DNA group was given vaccine 5 μg/kg+SAHA 20 mg/kg, the control group was given 100 μL phosphate solutions (PBS). Once every 3 days, total for 4 times. The tumor growth curve was drawn; the amount of CD8+T cells in peripheral blood of mice in each group was detected by flow cytometry; the effects of different doses of SAHA (25.0, 12.5 nmol/L) for the expression of H-2Kb of MHC class Ⅰ in TC-1 cells were detected by experiment in vitro. Results Compared with the other three groups, the tumor growth rate in SAHA and HPV16E7-DNA group was significantly slowed down, the amount of HPVE7 specific CD8+T cells in peripheral blood of mice was significantly increased (P < 0.05). In-vitro experiment showed that compared with control group, the expression of H-2Kb of MHC class Ⅰ in SAHA group was increased significantly (P < 0.05), while there was no significant difference between low dose of SAHA group and high dose of SAHA group (P > 0.05). Conclusion HDACI combined with HPV16E7-DNA vaccine comes into significant anti-tumor effects may be through up-regulating expression of MHC class Ⅰ of the tumor cells and activating the immune response of CD8+T cells, which is expected to be used in the immunotherapy of cervical cancer.
黄卓敏 李晴 姚秀华 金平. 组蛋白去乙酰化酶抑制剂联合HPV16E7-DNA疫苗治疗宫颈癌的效果及机制研究[J]. 中国医药导报, 2018, 15(5): 18-21.
HUANG Zhuomin LI Qing YAO Xiuhua JIN Ping. Effect of histone deacetylase inhibitor combined with HPV16E7-DNA vaccine in the treatment of cervical cancer and study on its mechanism. 中国医药导报, 2018, 15(5): 18-21.
[1] Small W Jr,Bacon MA,Bajaj A,et al. Cervical cancer:a global health crisis [J]. Cancer,2017,123(13):2404-2412.
[2] Shanmugasundaram S,You J. Targeting Persistent Human Papillomavirus Infection [J]. Viruses,2017,9(8):229-242.
[3] Lee SJ,Yang A,Wu TC,et al. Immunotherapy for human papillomavirus- associated disease and cervical cancer:review of clinical and translational research [J]. J Gynecol Oncol,2016,27(5):51-67.
[4] Shen L,Orillion A,Pili R. Histone deacetylase inhibitors as immune modulators in cancer therapeutics [J]. Epigenomics,2016,8(3):415-428.
[5] Chen W,Zheng R,Baade PD,et al. Cancer statistics in China,2015 [J]. CA Cancer J Clin,2016,66(2):115-132.
[6] Yang A,Jeang J,Cheng K,et al. Current state in the development of candidate therapeutic HPV vaccines [J]. Expert Rev Vaccines,2016,15(8):989-1007.
[7] Knoff J,Yang B,Hung CF,et al. Cervical Cancer:Development of Targeted Therapies Beyond Molecular Pathogenesis [J]. Curr Obstet Gynecol Rep,2014,3(1):18-32.
[8] Yang A,Peng S,Farmer E,et al. Enhancing antitumor immunogenicity of HPV16-E7 DNA vaccine by fusing DNA encoding E7-antigenic peptide to DNA encoding capsid protein L1 of Bovine papilloma virus [J]. Cell Biosci,2017, 7:46.
[9] van der Velden AW,Dougherty JT,Starnbach MN. Down-modulation of TCR expression by Salmonella entericaserovarTyphimurium [J]. J Immunol,2008,180(8):5569-5574.
[10] de Jong A,van Poelgeest MI,van der Hulst JM,et al. Human papillomavirus type 16- positive cervical cancer is associated with impaired CD4+ T- cell immunity against early antigens E2 and E6 [J]. Cancer Res,2004,64(15):5449-5455.
[11] de Boer MA,Jordanova ES,van Poelgeest MI,et al. Circu-lating human papillomavirus type 16 specific T-cells are associated with HLA Class Ⅰ expression on tumor cells,but not related to the amount of viral oncogene transcripts [J]. Int J Cancer,2007,121(12):2711-2715.
[12] Zhao LM,Zhang JH. Histone deacetylase inhibitors in tumor immunotherapy [J]. Curr Med Chem,2017. [Epub ahead of print]
[13] Briere D,Sudhakar N,Woods DM,et al. The class Ⅰ/Ⅳ HDAC inhibitor mocetinostat increases tumor antigen presentation,decreases immune suppressive cell types and augments checkpoint inhibitor therapy [J]. Cancer Immunol Immunother,2017. [Epub ahead of print]
[14] Turner TB,Meza-Perez S,Londoño A,et al. Epigenetic modifiers upregulate MHC Ⅱ and impede ovarian cancer tumor growth [J]. Oncotarget,2017,8(27):44159-44170.
[15] Adeegbe DO,Liu Y,Lizotte PH,et al. Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined HistoneDeacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer [J]. Cancer Discov,2017,7(8):852-867.
[16] Lee SY,Huang Z,Kang TH,et al. Histone deacetylase inhibitor AR-42 enhances E7-specific CD8+ T cell-mediated antitumor immunity induced by therapeutic HPV DNA vaccination [J]. J Mol Med(Berl),2013,91(10):1221-1231.
[17] Huang Z,Peng S,Knoff J,et al. Combination of proteasome and HDAC inhibitor enhances HPV16 E7-specific CD8+T cell immune response and antitumor effects in a preclinical cervical cancer model [J]. J Bio Med,2015, 22(7):2-10.
[18] Miyashita T,Miki K,Kamigaki T,et al. Low-dose valproic acid with low-dose gemcitabine augments MHC class Ⅰ-related chain A/B expression without inducing the release of soluble MHC class I-related chain A/B [J]. Oncol Lett,2017,14(5):5918-5926.
[19] He H,Liu X,Wang D,et al. SAHA inhibits the transcription initiation of HPV18 E6/E7 genes in HeLa cervical cancer cells [J]. Gen,2014,553(2):98-104.
[20] Bojilova ED,Weyn C,Antoine MH,et al. Extrachromosomal HPV-16 LCR transcriptional activation by HDACi opposed by cellular differentiation and DNA integration [J]. Oncotarget,2016,7(46):75 526-75 538.