Abstract
We report a method of inducing antigen production in dendritic cells by in vivo targeting with lentiviral vectors that specifically bind to the dendritic cell–surface protein DC-SIGN. To target dendritic cells, we enveloped the lentivector with a viral glycoprotein from Sindbis virus engineered to be DC-SIGN–specific. In vitro, this lentivector specifically transduced dendritic cells and induced dendritic cell maturation. A high frequency (up to 12%) of ovalbumin (OVA)-specific CD8+ T cells and a significant antibody response were observed 2 weeks after injection of a targeted lentiviral vector encoding an OVA transgene into naive mice. This approach also protected against the growth of OVA-expressing E.G7 tumors and induced regression of established tumors. Thus, lentiviral vectors targeting dendritic cells provide a simple method of producing effective immunity and may provide an alternative route for immunization with protein antigens.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Rosenberg, S.A., Yang, J.C. & Restifo, N.P. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909–915 (2004).
Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).
Banchereau, J. & Palucka, A.K. Dendritic cells as therapeutic vaccines against cancer. Nat. Rev. Immunol. 5, 296–306 (2005).
Figdor, C.G., de Vries, I.J., Lesterhuis, W.J. & Melief, C.J. Dendritic cell immunotherapy: mapping the way. Nat. Med. 10, 475–480 (2004).
Schuler, G., Schuler-Thurner, B. & Steinman, R.M. The use of dendritic cells in cancer immunotherapy. Curr. Opin. Immunol. 15, 138–147 (2003).
Ribas, A., Butterfield, L.H., Glaspy, J.A. & Economou, J.S. Cancer immunotherapy using gene-modified dendritic cells. Curr. Gene Ther. 2, 57–78 (2002).
Kirk, C.J. & Mule, J.J. Gene-modified dendritic cells for use in tumor vaccines. Hum. Gene Ther. 11, 797–806 (2000).
Song, W., Tong, Y., Carpenter, H., Kong, H.L. & Crystal, R.G. Persistent, antigen-specific, therapeutic antitumor immunity by dendritic cells genetically modified with an adenoviral vector to express a model tumor antigen. Gene Ther. 7, 2080–2086 (2000).
Gong, J. et al. Induction of antigen-specific antitumor immunity with adenovirus-transduced dendritic cells. Gene Ther. 4, 1023–1028 (1997).
Kaplan, J.M. et al. Induction of antitumor immunity with dendritic cells transduced with adenovirus vector-encoding endogenous tumor-associated antigens. J. Immunol. 163, 699–707 (1999).
Meyer zum Buschenfelde, C., Nicklisch, N., Rose-John, S., Peschel, C. & Bernhard, H. Generation of tumor-reactive CTL against the tumor-associated antigen HER2 using retrovirally transduced dendritic cells derived from CD34+ hemopoietic progenitor cells. J. Immunol. 165, 4133–4140 (2000).
Temme, A. et al. Efficient transduction and long-term retroviral expression of the melanoma-associated tumor antigen tyrosinase in CD34(+) cord blood-derived dendritic cells. Gene Ther. 9, 1551–1560 (2002).
Mangeot, P.E. et al. Development of minimal lentivirus vectors derived from simian immunodeficiency virus (SIVmac251) and their use for gene transfer into human dendritic cells. J. Virol. 74, 8307–8315 (2000).
Schroers, R. & Chen, S.Y. Lentiviral transduction of human dendritic cells. Methods Mol. Biol. 246, 451–459 (2004).
Esslinger, C., Romero, P. & MacDonald, H.R. Efficient transduction of dendritic cells and induction of a T-cell response by third-generation lentivectors. Hum. Gene Ther. 13, 1091–1100 (2002).
Barouch, D.H. & Nabel, G.J. Adenovirus vector-based vaccines for human immunodeficiency virus type 1. Hum. Gene Ther. 16, 149–156 (2005).
Shiver, J.W. & Emini, E.A. Recent advances in the development of HIV-1 vaccines using replication-incompetent adenovirus vectors. Annu. Rev. Med. 55, 355–372 (2004).
Tatsis, N. & Ertl, H.C. Adenoviruses as vaccine vectors. Mol. Ther. 10, 616–629 (2004).
Breckpot, K., Aerts, J.L. & Thielemans, K. Lentiviral vectors for cancer immunotherapy: transforming infectious particles into therapeutics. Gene Ther. 14, 847–862 (2007).
Esslinger, C. et al. In vivo administration of a lentiviral vaccine targets DCs and induces efficient CD8(+) T cell responses. J. Clin. Invest. 111, 1673–1681 (2003).
Kim, J.H. et al. Induction of therapeutic antitumor immunity by in vivo administration of a lentiviral vaccine. Hum. Gene Ther. 16, 1255–1266 (2005).
Dullaers, M. et al. Induction of effective therapeutic antitumor immunity by direct in vivo administration of lentiviral vectors. Gene Ther. 13, 630–640 (2006).
Cheng, C. et al. Mechanism of ad5 vaccine immunity and toxicity: fiber shaft targeting of dendritic cells. PLoS Pathog. 3, e25 (2007).
de Gruijl, T.D. et al. Prolonged maturation and enhanced transduction of dendritic cells migrated from human skin explants after in situ delivery of CD40-targeted adenoviral vectors. J. Immunol. 169, 5322–5331 (2002).
Belousova, N. et al. Genetically targeted adenovirus vector directed to CD40-expressing cells. J. Virol. 77, 11367–11377 (2003).
Bonifaz, L. et al. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J. Exp. Med. 196, 1627–1638 (2002).
Bonifaz, L.C. et al. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J. Exp. Med. 199, 815–824 (2004).
Trumpfheller, C. et al. Intensified and protective CD4+ T cell immunity in mice with anti-dendritic cell HIV gag fusion antibody vaccine. J. Exp. Med. 203, 607–617 (2006).
Tacken, P.J., de Vries, I.J., Torensma, R. & Figdor, C.G. Dendritic-cell immunotherapy: from ex vivo loading to in vivo targeting. Nat. Rev. Immunol. 7, 790–802 (2007).
Dakappagari, N. et al. Internalizing antibodies to the C-type lectins, L-SIGN and DC-SIGN, inhibit viral glycoprotein binding and deliver antigen to human dendritic cells for the induction of T cell responses. J. Immunol. 176, 426–440 (2006).
Geijtenbeek, T.B. et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100, 587–597 (2000).
Geijtenbeek, T.B. et al. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100, 575–585 (2000).
Geijtenbeek, T.B., van Vliet, S.J., Engering, A., t Hart, B.A. & van Kooyk, Y. Self- and nonself-recognition by C-type lectins on dendritic cells. Annu. Rev. Immunol. 22, 33–54 (2004).
Klimstra, W.B., Nangle, E.M., Smith, M.S., Yurochko, A.D. & Ryman, K.D. DC-SIGN and L-SIGN can act as attachment receptors for alphaviruses and distinguish between mosquito cell- and mammalian cell-derived viruses. J. Virol. 77, 12022–12032 (2003).
Strauss, J.H., Wang, K.S., Schmaljohn, A.L., Kuhn, R.J. & Strauss, E.G. Host-cell receptors for Sindbis virus. Arch. Virol. 9, 473–484 (1994).
Byrnes, A.P. & Griffin, D.E. Binding of Sindbis virus to cell surface heparan sulfate. J. Virol. 72, 7349–7356 (1998).
Morizono, K. et al. Lentiviral vector retargeting to P-glycoprotein on metastatic melanoma through intravenous injection. Nat. Med. 11, 346–352 (2005).
Yang, L., Bailey, L., Baltimore, D. & Wang, P. Targeting lentiviral vectors to specific cell types in vivo. Proc. Natl. Acad. Sci. USA 103, 11479–11484 (2006).
Lois, C., Hong, E.J., Pease, S., Brown, E.J. & Baltimore, D. Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science 295, 868–872 (2002).
Butler, S.L., Hansen, M.S. & Bushman, F.D. A quantitative assay for HIV DNA integration in vivo. Nat. Med. 7, 631–634 (2001).
Steinman, R.M., Hawiger, D. & Nussenzweig, M.C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).
Yang, L. & Baltimore, D. Long-term in vivo provision of antigen-specific T cell immunity by programming hematopoietic stem cells. Proc. Natl. Acad. Sci. USA 102, 4518–4523 (2005).
Zhou, T., Chen, Y., Hao, L. & Zhang, Y. DC-SIGN and immunoregulation. Cell Mol. Immunol. 3, 279–283 (2006).
Matsuno, K., Ezaki, T., Kudo, S. & Uehara, Y. A life stage of particle-laden rat dendritic cells in vivo: their terminal division, active phagocytosis, and translocation from the liver to the draining lymph. J. Exp. Med. 183, 1865–1878 (1996).
Shen, L., Evel-Kabler, K., Strube, R. & Chen, S.Y. Silencing of SOCS1 enhances antigen presentation by dendritic cells and antigen-specific anti-tumor immunity. Nat. Biotechnol. 22, 1546–1553 (2004).
Park, D., Lapteva, N., Seethammagari, M., Slawin, K.M. & Spencer, D.M. An essential role for Akt1 in dendritic cell function and tumor immunotherapy. Nat. Biotechnol. 24, 1581–1590 (2006).
Takahara, K. et al. Functional comparison of the mouse DC-SIGN, SIGNR1, SIGNR3 and Langerin, C-type lectins. Int. Immunol. 16, 819–829 (2004).
Powlesland, A.S. et al. Widely divergent biochemical properties of the complete set of mouse DC-SIGN-related proteins. J. Biol. Chem. 281, 20440–20449 (2006).
Acknowledgements
We are grateful to James Strauss for providing reagents and April Tai for a critical reading of the manuscript. This work was supported by a grant from the National Institute of Health (R01AI068978), a grant from the Bill and Melinda Gates Foundation through the Grand Challenges in Global Health Initiative, and by the Skirball Foundation.
Author information
Authors and Affiliations
Contributions
L.Y. and H.Y. designed research, performed experiments, discussed the results, wrote the paper. K.R., T.C., K.J., L.Z., A.E., A.W., D.Y. performed experiments. D.B. designed research, discussed the results, wrote the paper and provided financial support. P.W. designed research, performed experiments, discussed results, wrote the paper, provided financial support and coordinated the whole project.
Corresponding authors
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–6, Methods (PDF 782 kb)
Rights and permissions
About this article
Cite this article
Yang, L., Yang, H., Rideout, K. et al. Engineered lentivector targeting of dendritic cells for in vivo immunization. Nat Biotechnol 26, 326–334 (2008). https://doi.org/10.1038/nbt1390
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nbt1390
This article is cited by
-
Emerging strategies for biomaterial-assisted cancer immunotherapy
Korean Journal of Chemical Engineering (2022)
-
Designing spatial and temporal control of vaccine responses
Nature Reviews Materials (2021)
-
Emerging trends in immunotherapy for pediatric sarcomas
Journal of Hematology & Oncology (2019)
-
Antigen-presenting cell-targeted lentiviral vectors do not support the development of productive T-cell effector responses: implications for in vivo targeted vaccine delivery
Gene Therapy (2017)
-
Dendritic cell-based immunotherapy: a basic review and recent advances
Immunologic Research (2017)