Combination of proteasome and HDAC inhibitor enhances HPV16 E7-specific CD8+ T cell immune response and antitumor effects in a preclinical cervical cancer model

Journal of Biomedical Science

Chien-Fu Hung⁴  Tzyy-Choou Wu²  Benjamin Yang⁴  Sung Yong Lee³  Jayne Knoff⁴  Shiwen Peng⁴  Zhuomin Huang¹ 

[1] Department of Gynecology, Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, China;Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA;Department of Internal Medicine, Korea University Medical Center, Seoul, South Korea;Department of Pathology, Johns Hopkins Medical Institutions, CRB II Room 307, 1550 Orleans Street, Baltimore, 21231, MD, USA

关键词: Host immunity;    Antitumor;    Vorinostat;    SAHA;    Bortezomib;   

Others  :  1133570
DOI  :  10.1186/s12929-014-0111-1

 received in 2014-01-27, accepted in 2014-12-31,  发布年份 2015

【 摘 要 】

Background

Bortezomib, a proteasome inhibitor and suberoylanilide hydroxamic acid (SAHA, also known as Vorinostat), a histone deacetylase inhibitor, have been recognized as potent chemotherapeutic drugs. Bortezomib and SAHA are FDA-approved for the treatment of cutaneous T cell lymphoma and multiple myeloma/mantle cell lymphoma, respectively. Furthermore, the combination of the bortezomib and SAHA has been tested in a variety of preclinical models and in clinical trials and may be ideal for the treatment of cancer. However, it remains unclear how this treatment strategy affects the host immune response against tumors.

Results

Here, we used a well-defined E6/E7-expressing tumor model to examine how the immune system can be motivated to act against tumor cells expressing tumor antigens. We demonstrate that the combination of bortezomib and SAHA elicits potent antitumor effects in TC-1 tumor-bearing mice. Additionally, we are the first to show that treatment with bortezomib and SAHA leads to tumor-specific immunity by rendering tumor cells more susceptible to killing by antigen-specific CD8+ T cells than treatment with either drug alone.

Conclusions

The current study serves an important foundation for the future clinical application of both drugs for the treatment of cervical cancer.

【 授权许可】

   
2015 Huang et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Pellom ST Jr, Shanker A: Development of Proteasome Inhibitors as Therapeutic Drugs. J Clin Cell Immunol 2012, S5:5.
• [2]Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, et al.: Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 2002, 99:14374-9.
• [3]Spisek R, Charalambous A, Mazumder A, Vesole DH, Jagannath S, Dhodapkar MV: Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood 2007, 109:4839-45.
• [4]Chang CL, Hsu YT, Wu CC, Yang YC, Wang C, Wu TC, et al.: Immune mechanism of the antitumor effects generated by bortezomib. J Immunol 2012, 189:3209-20.
• [5]Wade PA: Transcriptional control at regulatory checkpoints by histone deacetylases: molecular connections between cancer and chromatin. Hum Mol Genet 2001, 10:693-8.
• [6]Roy S, Packman K, Jeffrey R, Tenniswood M: Histone deacetylase inhibitors differentially stabilize acetylated p53 and induce cell cycle arrest or apoptosis in prostate cancer cells. Cell Death Differ 2005, 12:482-91.
• [7]Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H, et al.: Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther 2003, 2:971-84.
• [8]Marks PA, Dokmanovic M: Histone deacetylase inhibitors: discovery and development as anticancer agents. Expert Opin Investig Drugs 2005, 14:1497-511.
• [9]Bolden JE, Peart MJ, Johnstone RW: Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006, 5:769-84.
• [10]Magner WJ, Kazim AL, Stewart C, Romano MA, Catalano G, Grande C, et al.: Activation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitors. J Immunol 2000, 165:7017-24.
• [11]Mann BS, Johnson JR, He K, Sridhara R, Abraham S, Booth BP, et al.: Vorinostat for treatment of cutaneous manifestations of advanced primary cutaneous T-cell lymphoma. Clin Cancer Res 2007, 13:2318-22.
• [12]Lin Z, Bazzaro M, Wang MC, Chan KC, Peng S, Roden RB: Combination of proteasome and HDAC inhibitors for uterine cervical cancer treatment. Clin Cancer Res 2009, 15:570-7.
• [13]Brehm A, Nielsen SJ, Miska EA, McCance DJ, Reid JL, Bannister AJ, et al.: The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth. EMBO J 1999, 18:2449-58.
• [14]Lin KY, Guarnieri FG, Staveley-O’Carroll KF, Levitsky HI, August JT, Pardoll DM, et al.: Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res 1996, 56:21-6.
• [15]Kim D, Hung CF, Wu TC: Monitoring the trafficking of adoptively transferred antigen- specific CD8-positive T cells in vivo, using noninvasive luminescence imaging. Hum Gene Ther 2007, 18:575-88.
• [16]Wang TL, Ling M, Shih IM, Pham T, Pai SI, Lu Z, et al.: Intramuscular administration of E7-transfected dendritic cells generates the most potent E7-specific anti-tumor immunity. Gene Ther 2000, 7:726-33.
• [17]Sato A, Asano T, Ito K, Asano T: Vorinostat and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells. J Urol 2012, 188:2410-8.
• [18]Asklund T, Kvarnbrink S, Holmlund C, Wibom C, Bergenheim T, Henriksson R, et al.: Synergistic killing of glioblastoma stem-like cells by bortezomib and HDAC inhibitors. Anticancer Res 2012, 32:2407-13.
• [19]Campbell RA, Sanchez E, Steinberg J, Shalitin D, Li ZW, Chen H, et al.: Vorinostat enhances the antimyeloma effects of melphalan and bortezomib. Eur J Haematol 2010, 84:201-11.
• [20]Zhang QL, Wang L, Zhang YW, Jiang XX, Yang F, Wu WL, et al.: The proteasome inhibitor bortezomib interacts synergistically with the histone deacetylase inhibitor suberoylanilide hydroxamic acid to induce T-leukemia/lymphoma cells apoptosis. Leukemia 2009, 23:1507-14.
• [21]Dimopoulos M, Siegel DS, Lonial S, Qi J, Hajek R, Facon T, et al.: Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol 2013, 14:1129-40.
• [22]Hoang T, Campbell TC, Zhang C, Kim K, Kolesar JM, Oettel KR, et al.: Vorinostat and bortezomib as third-line therapy in patients with advanced non-small cell lung cancer: a Wisconsin Oncology Network Phase II study. Invest New Drugs 2014, 32(1):195-9.
• [23]Muscal JA, Thompson PA, Horton TM, Ingle AM, Ahern CH, McGovern RM, et al.: A phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors: a Children’s Oncology Group phase I consortium study (ADVL0916). Pediatr Blood Cancer 2013, 60:390-5.
• [24]Deming DA, Ninan J, Bailey HH, Kolesar JM, Eickhoff J, Reid JM, et al.: A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors. Invest New Drugs 2014, 32(2):323-9.
• [25]Schelman WR, Traynor AM, Holen KD, Kolesar JM, Attia S, Hoang T, et al.: A phase I study of vorinostat in combination with bortezomib in patients with advanced malignancies. Invest New Drugs 2013, 31(6):1539-46.
• [26]Joffre OP, Segura E, Savina A, Amigorena S: Cross-presentation by dendritic cells. Nat Rev Immunol 2012, 12:557-69.
• [27]Tseng CW, Monie A, Wu CY, Huang B, Wang MC, Hung CF, et al.: Treatment with proteasome inhibitor bortezomib enhances antigen-specific CD8+ T-cell-mediated antitumor immunity induced by DNA vaccination. J Mol Med (Berl) 2008, 86:899-908.