Adenovirus co‑expressing CD40 ligand and interleukin (IL)‑2 contributes to maturation of dendritic cells and production of IL‑12

Guo,Zhi; Gao,Hong‑Yan; Zhang,Tian‑Yang; Lou,Jin‑Xing; Yang,Kai; Liu,Xiao‑Dong; He,Xue‑Peng; Chen,Hui‑Ren

doi:10.3892/br.2016.773

Adenovirus co‑expressing CD40 ligand and interleukin (IL)‑2 contributes to maturation of dendritic cells and production of IL‑12

Authors:
- Zhi Guo
- Hong‑Yan Gao
- Tian‑Yang Zhang
- Jin‑Xing Lou
- Kai Yang
- Xiao‑Dong Liu
- Xue‑Peng He
- Hui‑Ren Chen
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Affiliations: Department of Hematology, Beijing Military General Hospital, Beijing 100700, P.R. China
Published online on: October 6, 2016 https://doi.org/10.3892/br.2016.773
Pages: 567-573

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Abstract

The aim of the present study was to construct a chimeric adenovirus (Ad)5/F35 co-expressing human CD4O ligand (CD4OL) and interleukin (IL)‑2 (Ad5/F35 CD40L‑IL‑2). The infection efficiency to human monocyte‑derived dendritic cells (Mo‑DCs), expression of genes, phenotype changes and IL‑12 production of Mo‑DC by Ad5/F35 CD40L‑IL‑2 were investigated. CD40L and IL‑2 from total RNA extracted from human peripheral blood mononuclear cells (PBMCs) were cloned by reverse transcription‑polymerase chain reaction and used to construct Ad5/F35 CD40L‑IL‑2. The infection efficiency, expression of CD40L, and phenotype changes of Mo‑DC infected with Ad5/F35 CD40L‑IL‑2 were analyzed using flow cytometry. The quantities of IL‑2 and IL‑12 in the supernatants of Mo‑DC following infection of Ad5/F35 CD40L‑IL‑2 were measured by enzyme‑linked immunosorbent assay. The CD40L and IL‑2 genes were successfully cloned and the Ad5/F35 CD40L‑IL‑2 was constructed. Ad5/F35 CD40L‑IL‑2 efficiently infected Mo‑DCs with an infection efficiency of >75%, and the infected Mo‑DCs expressed CD40L and secreted IL‑2. The expression levels of cluster of differentiation (CD)80, CD86, CD40, and human leukocyte antigen‑antigen D related on Mo‑DC were moderate; however, CD83 was low prior to infection of Ad5/F35 CD40L‑IL‑2. Those molecules, particularly CD83, were markedly upregulated 24 h after the infection. Increasing quantities of IL‑12 in the supernatants were detected subsequent to infection at different time points in a time‑dependent manner. Thus, Ad5/F35 CD40L‑IL‑2 efficiently infected human Mo‑DCs and its products, CD40L and IL‑2, were subsequently expressed. In addition, infection with Ad5/F35 CD40L‑IL‑2 stimulated the maturation of Mo‑DC and high levels of IL‑12 production.

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1	Cun Y, Zhang Q, Xiong C, Li M, Dai N, Zhang S and Wang D: Combined use of adenoviral vector Ad5/F35-mediated APE1 siRNA enhances the therapeutic efficacy of adenoviral-mediated p53 gene transfer in hepatoma cells in vitro and in vivo. Oncol Rep. 29:2197–2204. 2013.PubMed/NCBI
2	Kim SY, Kang S, Song JJ and Kim JH: The effectiveness of the oncolytic activity induced by Ad5/F35 adenoviral vector is dependent on the cumulative cellular conditions of survival and autophagy. Int J Oncol. 42:1337–1348. 2013.PubMed/NCBI
3	Hu X, Cao Y, Meng Y and Hou M: A novel modulation of structural and functional changes of mouse bone marrow derived dendritic cells (BMDCs) by interleukin-2(IL-2). Hum Vaccin Immunother. 11:516–521. 2015. View Article : Google Scholar : PubMed/NCBI
4	de Vries IJ, Lesterhuis WJ, Scharenborg NM, Engelen LP, Ruiter DJ, Gerritsen MJ, Croockewit S, Britten CM, Torensma R, Adema GJ, et al: Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients. Clin Cancer Res. 9:5091–5100. 2003.PubMed/NCBI
5	Kim R, Emi M and Tanabe K: Functional roles of immature dendritic cells in impaired immunity of solid tumour and their targeted strategies for provoking tumour immunity. Clin Exp Immunol. 146:189–196. 2006. View Article : Google Scholar : PubMed/NCBI
6	Castiello L, Sabatino M, Jin P, Clayberger C, Marincola FM, Krensky AM and Stroncek DF: Monocyte-derived DC maturation strategies and related pathways: A transcriptional view. Cancer Immunol Immunother. 60:457–466. 2011. View Article : Google Scholar : PubMed/NCBI
7	Mossoba ME and Medin JA: Cancer immunotherapy using virally transduced dendritic cells: Animal studies and human clinical trials. Expert Rev Vaccines. 5:717–732. 2006. View Article : Google Scholar : PubMed/NCBI
8	Cavallini C, Lovato O, Bertolaso A, Pacelli L, Zoratti E, Zanolin E, Krampera M, Zamò A, Tecchio C, Cassatella MA, et al: The TNF-family cytokine TL1A inhibits proliferation of human activated B cells. PLoS One. 8:e601362013. View Article : Google Scholar : PubMed/NCBI
9	Erdmann M and Schuler-Thurner B: Towards a standardized protocol for the generation of monocyte-derived dendritic cell vaccines. Methods Mol Biol. 595:149–163. 2010. View Article : Google Scholar : PubMed/NCBI
10	Guo Z, Liu H, He XP, Tan XH, Zhou Y, Chen X, Shi YJ, Liu XD and Chen HR: A clinical study of cytokine-induced killer cells for the treatment of refractory lymphoma. Oncol Lett. 2:531–536. 2011.PubMed/NCBI
11	Boudreau JE, Bonehill A, Thielemans K and Wan Y: Engineering dendritic cells to enhance cancer immunotherapy. Mol Ther. 19:841–853. 2011. View Article : Google Scholar : PubMed/NCBI
12	Morelli AE, Zahorchak AF, Larregina AT, Colvin BL, Logar AJ, Takayama T, Falo LD and Thomson AW: Cytokine production by mouse myeloid dendritic cells in relation to differentiation and terminal maturation induced by lipopolysaccharide or CD40 ligation. Blood. 98:1512–1523. 2001. View Article : Google Scholar : PubMed/NCBI
13	Kelleher M and Beverley PC: Lipopolysaccharide modulation of dendritic cells is insufficient to mature dendritic cells to generate CTLs from naive polyclonal CD8⁺ T cells in vitro, whereas CD40 ligation is essential. J Immunol. 167:6247–6255. 2001. View Article : Google Scholar : PubMed/NCBI
14	Tcherepanova IY, Adams MD, Feng X, Hinohara A, Horvatinovich J, Calderhead D, Healey D and Nicolette CA: Ectopic expression of a truncated CD40L protein from synthetic post-transcriptionally capped RNA in dendritic cells induces high levels of IL-12 secretion. BMC Mol Biol. 9:902008. View Article : Google Scholar : PubMed/NCBI
15	Hernandez MG, Shen L and Rock KL: CD40-CD40 ligand interaction between dendritic cells and CD8⁺ T cells is needed to stimulate maximal T cell responses in the absence of CD4⁺ T cell help. J Immunol. 178:2844–2852. 2007. View Article : Google Scholar : PubMed/NCBI
16	Thacker EE, Nakayama M, Smith BF, Bird RC, Muminova Z, Strong TV, Timares L, Korokhov N, O'Neill AM, de Gruijl TD, et al: A genetically engineered adenovirus vector targeted to CD40 mediates transduction of canine dendritic cells and promotes antigen-specific immune responses in vivo. Vaccine. 27:7116–7124. 2009. View Article : Google Scholar : PubMed/NCBI
17	Kikuchi T, Moore MA and Crystal RG: Dendritic cells modified to express CD40 ligand elicit therapeutic immunity against preexisting murine tumors. Blood. 96:91–99. 2000.PubMed/NCBI
18	Tada Y, O-Wang J, Yu L, Shimozato O, Wang YQ, Takiguchi Y, Tatsumi K, Kuriyama T, Takenaga K, Sakiyama S, et al: T-cell-dependent antitumor effects produced by CD40 ligand expressed on mouse lung carcinoma cells are linked with the maturation of dendritic cells and secretion of a variety of cytokines. Cancer Gene Ther. 10:451–456. 2003. View Article : Google Scholar : PubMed/NCBI
19	Wolf B, Schwarzer A, Côté AL, Hampton TH, Schwaab T, Huarte E, Tomlinson CR, Gui J, Fisher JL, Fadul CE, et al: Gene expression profile of peripheral blood lymphocytes from renal cell carcinoma patients treated with IL-2, interferon-α and dendritic cell vaccine. PLoS One. 7:e502212012. View Article : Google Scholar : PubMed/NCBI
20	Stax AM, Crul C, Kamerling SW, Schlagwein N, van der Geest RN, Woltman AM and van Kooten C: CD40L stimulation of rat dendritic cells specifically favors the IL-12/IL-10 ratio resulting in a strong T cell stimulatory capacity. Mol Immunol. 45:2641–2650. 2008. View Article : Google Scholar : PubMed/NCBI
21	Nagy ZS, Ross JA, Rodriguez G, Balint BL, Szeles L, Nagy L and Kirken RA: Genome wide mapping reveals PDE4B as an IL-2 induced STAT5 target gene in activated human PBMCs and lymphoid cancer cells. PLoS One. 8:e573262013. View Article : Google Scholar : PubMed/NCBI
22	Gonzalez-Carmona MA, Lukacs-Kornek V, Timmerman A, Shabani S, Kornek M, Vogt A, Yildiz Y, Sievers E, Schmidt-Wolf IG, Caselmann WH, et al: CD40ligand-expressing dendritic cells induce regression of hepatocellular carcinoma by activating innate and acquired immunity in vivo. Hepatology. 48:157–168. 2008. View Article : Google Scholar : PubMed/NCBI
23	DeBenedette MA, Calderhead DM, Tcherepanova IY, Nicolette CA and Healey DG: Potency of mature CD40L RNA electroporated dendritic cells correlates with IL-12 secretion by tracking multifunctional CD8(+)/CD28(+) cytotoxic T-cell responses in vitro. J Immunother. 34:45–57. 2011. View Article : Google Scholar : PubMed/NCBI
24	Rousseau RF, Biagi E, Dutour A, Yvon ES, Brown MP, Lin T, Mei Z, Grilley B, Popek E, Heslop HE, et al: Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation. Blood. 107:1332–1341. 2006. View Article : Google Scholar : PubMed/NCBI
25	Balamotis MA, Huang K and Mitani K: Efficient delivery and stable gene expression in a hematopoietic cell line using a chimeric serotype 35 fiber pseudotyped helper-dependent adenoviral vector. Virology. 324:229–237. 2004. View Article : Google Scholar : PubMed/NCBI
26	Gaggar A, Shayakhmetov DM and Lieber A: CD46 is a cellular receptor for group B adenoviruses. Nat Med. 9:1408–1412. 2003. View Article : Google Scholar : PubMed/NCBI
27	Ophorst OJ, Kostense S, Goudsmit J, De Swart RL, Verhaagh S, Zakhartchouk A, Van Meijer M, Sprangers M, Van Amerongen G, Yüksel S, et al: An adenoviral type 5 vector carrying a type 35 fiber as a vaccine vehicle: DC targeting, cross neutralization, and immunogenicity. Vaccine. 22:3035–3044. 2004. View Article : Google Scholar : PubMed/NCBI
28	Vitoriano-Souza J, Moreira N, Teixeira-Carvalho A, Carneiro CM, Siqueira FA, Vieira PM, Giunchetti RC, Moura SA, Fujiwara RT, Melo MN, et al: Cell recruitment and cytokines in skin mice sensitized with the vaccine adjuvants: Saponin, incomplete Freund's adjuvant, and monophosphoryl lipid A. PLoS One. 7:e407452012. View Article : Google Scholar : PubMed/NCBI
29	Yang S, Cohen CJ, Peng PD, Zhao Y, Cassard L, Yu Z, Zheng Z, Jones S, Restifo NP, Rosenberg SA, et al: Development of optimal bicistronic lentiviral vectors facilitates high-level TCR gene expression and robust tumor cell recognition. Gene Ther. 15:1411–1423. 2008. View Article : Google Scholar : PubMed/NCBI
30	Ngoi SM, Chien AC and Lee CG: Exploiting internal ribosome entry sites in gene therapy vector design. Curr Gene Ther. 4:15–31. 2004. View Article : Google Scholar : PubMed/NCBI