Abstract
Aim:
Adenovirus-mediated gene therapy is a novel therapeutic approach for the treatment of cancer, in which replication of the virus itself is the anticancer method. However, the success of this novel therapy is limited due to inefficient delivery of the virus to the target sites. In this study, we used dendritic cells (DCs) as carriers for conditionally replicating adenoviruses (CRAds) in targeting prostate carcinoma (PCa).
Methods:
Four types of CRAds, including Ad-PC (without PCa-specific promoter and a recombinant human tumor necrosis factor, rmhTNF, sequence), Ad-PC-rmhTNF (without PCa-specific promoter), Ad-PPC-NCS (without an rmhTNF sequence) and Ad-PPC-rmhTNF, were constructed. The androgen-insensitive mouse PCa RM-1 cells were co-cultured with CRAd-loading DCs, and the viability of RM-1 cells was examined using MTT assay. The in vivo effects of CRAd-loading DCs on PCa were evaluated in RM-1 xenograft mouse model.
Results:
Two PCa-specific CRAds (Ad-PPC-NCS, Ad-PPC-rmhTNF) exhibited more potent suppression on the viability of RM-1 cells in vitro than the PCa-non-specific CRAds (Ad-PC, Ad-PC-rmhTNF). In PCa-bearing mice, intravenous injection of the PCa-specific CRAd-loading DCs significantly inhibited the growth of xenografted tumors, extended the survival time, and induced T-cell activation. Additionally, the rmhTNF-containing CRAds exhibited greater tumor killing ability than CRAds without rmhTNF.
Conclusion:
DCs may be an effective vector for the delivery of CRAds in the treatment of PCa.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Siegel R, Naishadham D, Jemal A . Cancer statistics, 2013. CA Cancer J Clin 2013; 63: 11–30.
Djavan B, Moul JW, Zlotta A, Remzi M, Ravery V . PSA progression following radical prostatectomy and radiation therapy: new standards in the new Millennium. Eur Urol 2003; 43: 12–27.
Jeet V, Tevz G, Lehman M, Hollier B, Nelson C . Elevated YKL40 is associated with advanced prostate cancer (PCa) and positively regulates invasion and migration of PCa cells. Endocr Relat Cancer 2014; 21: 723–37.
Schenk E, Essand M, Bangma CH, Barber C, Behr JP, Briggs S, et al. Clinical adenoviral gene therapy for prostate cancer. Hum Gene Ther 2010; 21: 807–13.
Cheng WS, Dzojic H, Nilsson B, Totterman TH, Essand M . An oncolytic conditionally replicating adenovirus for hormone-dependent and hormone-independent prostate cancer. Cancer Gene Ther 2006; 13: 13–20.
Ilett EJ, Prestwich RJ, Kottke T, Errington F, Thompson JM, Harrington KJ, et al. Dendritic cells and T cells deliver oncolytic reovirus for tumour killing despite pre-existing anti-viral immunity. Gene Ther 2009; 16: 689–99.
Schmid MA, Harris E . Monocyte recruitment to the dermis and differentiation to dendritic cells increases the targets for dengue virus replication. PLoS Pathog 2014; 10: e1004541.
Xu H, Cao X . Dendritic cell vaccines in cancer immunotherapy: from biology to translational medicine. Front Med 2011; 5: 323–32.
Moodycliffe AM, Shreedhar V, Ullrich SE, Walterscheid J, Bucana C, Kripke ML, et al. CD40-CD40 ligand interactions in vivo regulate migration of antigen-bearing dendritic cells from the skin to draining lymph nodes. J Exp Med 2000; 191: 2011–20.
Pesonen S, Diaconu I, Kangasniemi L, Ranki T, Kanerva A, Pesonen SK, et al. Oncolytic immunotherapy of advanced solid tumors with a CD40L-expressing replicating adenovirus: assessment of safety and immunologic responses in patients. Cancer Res 2012; 72: 1621–31.
Baley PA, Yoshida K, Qian W, Sehgal I, Thompson TC . Progression to androgen insensitivity in a novel in vitro mouse model for prostate cancer. J Steroid Biochem Mol Biol 1995; 52: 403–13.
Williams BJ, Bhatia S, Adams LK, Boling S, Carroll JL, Li XL, et al. Dendritic cell based PSMA immunotherapy for prostate cancer using a CD40-targeted adenovirus vector. PLoS One 2012; 7: e46981.
Yan Z, Zhao N, Wang Z, Li B, Bao C, Shi J, et al. A mutated human tumor necrosis factor-alpha improves the therapeutic index in vitro and in vivo. Cytotherapy 2006; 8: 415–23.
Huang JH, Zhang SN, Choi KJ, Choi IK, Kim JH, Lee MG, et al. Therapeutic and tumor-specific immunity induced by combination of dendritic cells and oncolytic adenovirus expressing IL-12 and 4-1BBL. Mol Ther 2010; 18: 264–74.
Wu H, Kumar A, Miao H, Holden-Wiltse J, Mosmann TR, Livingstone AM, et al. Modeling of influenza-specific CD8+ T cells during the primary response indicates that the spleen is a major source of effectors. J Immunol 2011; 187: 4474–82.
Liu B, Woltman AM, Janssen HL, Boonstra A . Modulation of dendritic cell function by persistent viruses. J Leukoc Biol 2009; 85: 205–14.
Kim HP, Lee YS, Park JH, Kim YJ . Transcriptional and epigenetic networks in the development and maturation of dendritic cells. Epigenomics 2013; 5: 195–204.
Wolters T, Roobol MJ, van Leeuwen PJ, van den Bergh RC, Hoedemaeker RF, van Leenders GJ, et al. Should pathologists routinely report prostate tumour volume? The prognostic value of tumour volume in prostate cancer. Eur Urol 2010; 57: 821–9.
Bemelmans MH, van Tits LJ, Buurman WA . Tumor necrosis factor: function, release and clearance. Crit Rev Immunol 1996; 16: 1–11.
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (No 81272846) and the Foundation from the Second Affiliated Hospital, Xi-an Jiaotong University Medical College (No YJ(ZD)201107 and YJ(ZD)201318).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Li, Zl., Liang, X., Li, Hc. et al. Dendritic cells serve as a “Trojan horse” for oncolytic adenovirus delivery in the treatment of mouse prostate cancer. Acta Pharmacol Sin 37, 1121–1128 (2016). https://doi.org/10.1038/aps.2016.59
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2016.59
Keywords
This article is cited by
-
Zika virus enhances monocyte adhesion and transmigration favoring viral dissemination to neural cells
Nature Communications (2019)
