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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 volume 24, pages 370–375 (2017)Cite this article

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Abstract

Targeting transgene expression specifically to antigen-presenting cells (APCs) has been put forward as a promising strategy to direct the immune system towards immunity. We developed the nanobody-display technology to restrict the tropism of lentiviral vectors (LVs) to APCs. However, we observed that immunization with APC-targeted LVs (DC2.1-LVs) did not evoke strong antigen-specific T-cell immunity when compared to immunization with broad tropism LVs (VSV.G-LVs). In this study, we report that VSV.G-LVs are more immunogenic than DC2.1-LVs because they transduce stromal cells, which has a role in activating antigen-specific T cells. Moreover, VSV.G-LVs trigger a pro-inflammatory innate immune response through transduction of APCs and stromal cells, while DC2.1-LVs trigger a type I interferon response with anti-viral capacity. These findings question the rationale of targeting LVs to APCs and argue for the development of VSV.G-LVs with an improved safety profile.

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References

  1. Wayteck L, Breckpot K, Demeester J, De Smedt SC, Raemdonck K . A personalized view on cancer immunotherapy. Cancer Lett 2013; 352: 113–125.

    Article  Google Scholar 

  2. Breckpot K, Dullaers M, Bonehill A, van Meirvenne S, Heirman C, de Greef C et al. Lentivirally transduced dendritic cells as a tool for cancer immunotherapy. J Gene Med 2003; 5: 654–667.

    Article  CAS  Google Scholar 

  3. Goyvaerts C, Breckpot K . Pros and cons of antigen-presenting cell targeted tumor vaccines. J Immunol Res 2015; 2015: 785634, 1–18.

    Article  Google Scholar 

  4. Breckpot K, Aerts JL, Thielemans K . Lentiviral vectors for cancer immunotherapy: transforming infectious particles into therapeutics. Gene Therapy 2007; 14: 847–862.

    Article  CAS  Google Scholar 

  5. Dyall J, Latouche JB, Schnell S, Sadelain M . Lentivirus-transduced human monocyte-derived dendritic cells efficiently stimulate antigen-specific cytotoxic T lymphocytes. Blood 2001; 97: 114–121.

    Article  CAS  Google Scholar 

  6. Firat H, Zennou V, Garcia-Pons F, Ginhoux F, Cochet M, Danos O et al. Use of a lentiviral flap vector for induction of CTL immunity against melanoma. Perspectives for immunotherapy. J Gene Med 2002; 4: 38–45.

    Article  Google Scholar 

  7. Dullaers M, Van Meirvenne S, Heirman C, Straetman L, Bonehill A, Aerts JL et al. Induction of effective therapeutic antitumor immunity by direct in vivo administration of lentiviral vectors. Gene Ther 2006; 13: 630–640.

    Article  CAS  Google Scholar 

  8. Esslinger C, Chapatte L, Finke D, Miconnet I, Guillaume P, Levy F et al. In vivo administration of a lentiviral vaccine targets DCs and induces efficient CD8(+) T cell responses. J Clin Invest 2003; 111: 1673–1681.

    Article  CAS  Google Scholar 

  9. Breckpot K, Emeagi P, Dullaers M, Michiels A, Heirman C, Thielemans K . Activation of immature monocyte-derived dendritic cells after transduction with high doses of lentiviral vectors. Hum Gene Ther 2007; 18: 536–546.

    Article  CAS  Google Scholar 

  10. Breckpot K, Escors D, Arce F, Lopes L, Karwacz K, Van Lint S et al. HIV-1 lentiviral vector immunogenicity is mediated by Toll-like receptor 3 (TLR3) and TLR7. J Virol 2010; 84: 5627–5636.

    Article  CAS  Google Scholar 

  11. Brown BD, Sitia G, Annoni A, Hauben E, Sergi LS, Zingale A et al. In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promotes vector clearance. Blood 2007; 109: 2797–2805.

    Article  CAS  Google Scholar 

  12. Yang L, Yang H, Rideout K, Cho T, Joo KI, Ziegler L et al. Engineered lentivector targeting of dendritic cells for in vivo immunization. Nat Biotechnol 2008; 26: 326–334.

    Article  CAS  Google Scholar 

  13. Yang HG, Hu BL, Xiao L, Wang P . Dendritic cell-directed lentivector vaccine induces antigen-specific immune responses against murine melanoma. Cancer Gene Ther 2011; 18: 370–380.

    Article  CAS  Google Scholar 

  14. Xiao L, Joo KI, Lim M, Wang P . Dendritic cell-directed vaccination with a lentivector encoding PSCA for prostate cancer in mice. PLoS One 2012; 7: e48866.

    Article  CAS  Google Scholar 

  15. Anliker B, Abel T, Kneissl S, Hlavaty J, Caputi A, Brynza J et al. Specific gene transfer to neurons, endothelial cells and hematopoietic progenitors with lentiviral vectors. Nat Methods 2010; 7: 929–935.

    Article  CAS  Google Scholar 

  16. Zhang XY, Kutner RH, Bialkowska A, Marino MP, Klimstra WB, Reiser J . Cell-specific targeting of lentiviral vectors mediated by fusion proteins derived from Sindbis virus, vesicular stomatitis virus, or avian sarcoma/leukosis virus. Retrovirology 2010; 7: 3.

    Article  Google Scholar 

  17. Ageichik A, Buchholz CJ, Collins MK . Lentiviral vectors targeted to MHC II are effective in immunization. Hum Gene Ther 2011; 22: 1249–1254.

    Article  CAS  Google Scholar 

  18. Goyvaerts C, Dingemans J, De Groeve K, Heirman C, Van Gulck E, Vanham G et al. Targeting of human antigen-presenting cell subsets. J Virol 2013; 87: 11304–11308.

    Article  CAS  Google Scholar 

  19. Goyvaerts C, De Groeve K, Dingemans J, Van Lint S, Robays L, Heirman C et al. Development of the nanobody display technology to target lentiviral vectors to antigen-presenting cells. Gene Therapy 2012; 19: 1133–1140.

    Article  CAS  Google Scholar 

  20. Goyvaerts C, Kurt de G, Van Lint S, Heirman C, Van Ginderachter JA, De Baetselier P et al. Immunogenicity of targeted lentivectors. Oncotarget 2014; 5: 704–715.

    Article  Google Scholar 

  21. Goyvaerts C, Broos K, Escors D, Heirman C, Raes G, De Baetselier P et al. The transduction pattern of IL-12-encoding lentiviral vectors shapes the immunological outcome. Eur J Immunol 2015; 45: 3351–3361.

    Article  CAS  Google Scholar 

  22. Cire S, Da Rocha S, Yao R, Fisson S, Buchholz CJ, Collins MK et al. Immunization of mice with lentiviral vectors targeted to MHC class II+ cells is due to preferential transduction of dendritic cells In Vivo. PLoS One 2014; 9: e101644.

    Article  Google Scholar 

  23. Cire S, Da Rocha S, Ferrand M, Collins MK, Galy A . In vivo gene delivery to lymph node stromal cells leads to transgene-specific CD8+ T cell anergy in mice. Mol Ther 2016; 24: 1965–1973.

    Article  CAS  Google Scholar 

  24. Yoo S, Ha SJ . Generation of tolerogenic dendritic cells and their therapeutic applications. Immune Netw 2016; 16: 52–60.

    Article  Google Scholar 

  25. Annoni A, Brown BD, Cantore A, Sergi LS, Naldini L, Roncarolo MG . In vivo delivery of a microRNA-regulated transgene induces antigen-specific regulatory T cells and promotes immunologic tolerance. Blood 2009; 114: 5152–5161.

    Article  CAS  Google Scholar 

  26. Hirosue S, Dubrot J . Modes of antigen presentation by lymph node stromal cells and their immunological implications. Front Immunol 2015; 6: 446.

    Article  Google Scholar 

  27. Kedl RM, Tamburini BA . Antigen archiving by lymph node stroma: a novel function for the lymphatic endothelium. Eur J Immunol 2015; 45: 2721–2729.

    Article  CAS  Google Scholar 

  28. Li L, Kim S, Herndon JM, Goedegebuure P, Belt BA, Satpathy AT et al. Cross-dressed CD8alpha+/CD103+ dendritic cells prime CD8+ T cells following vaccination. Proc Natl Acad Sci USA 2012; 109: 12716–12721.

    Article  CAS  Google Scholar 

  29. Akhrymuk I, Frolov I, Frolova EI . Both RIG-I and MDA5 detect alphavirus replication in concentration-dependent mode. Virology 2016; 487: 230–241.

    Article  CAS  Google Scholar 

  30. Kawai T, Akira S . Innate immune recognition of viral infection. Nat Immunol 2006; 7: 131–137.

    Article  CAS  Google Scholar 

  31. Lienenklaus S, Cornitescu M, Zietara N, Lyszkiewicz M, Gekara N, Jablonska J et al. Novel reporter mouse reveals constitutive and inflammatory expression of IFN-beta In Vivo. J Immunol 2009; 183: 3229–3236.

    Article  CAS  Google Scholar 

  32. Dullaers M, Breckpot K, Van Meirvenne S, Bonehill A, Tuyaerts S, Michiels A et al. Side-by-side comparison of lentivirally transduced and mRNA-electroporated dendritic cells: implications for cancer immunotherapy protocols. Mol Ther 2004; 10: 768–779.

    Article  CAS  Google Scholar 

  33. Schoggins JW, Rice CM . Interferon-stimulated genes and their antiviral effector functions. Curr Opin Virol 2011; 1: 519–525.

    Article  CAS  Google Scholar 

  34. Van Lint S, Goyvaerts C, Maenhout S, Goethals L, Disy A, Benteyn D et al. Preclinical evaluation of TriMix and antigen mRNA-based antitumor therapy. Cancer Res 2012; 72: 1661–1671.

    Article  CAS  Google Scholar 

  35. Keyaerts M, Verschueren J, Bos TJ, Tchouate-Gainkam LO, Peleman C, Breckpot K et al. Dynamic bioluminescence imaging for quantitative tumour burden assessment using IV or IP administration of D: -luciferin: effect on intensity, time kinetics and repeatability of photon emission. Eur J Nucl Med Mol Imaging 2008; 35: 999–1007.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Carlo Heirman, Elsy Vaeremans and Petra Roman for cloning and technical assistance. We furthermore thank Claude Libert for providing the IFNAR−/− mice. This work was supported by grants from the following funding agencies: Stichting tegen Kanker, Kom op tegen Kanker, Agency for Innovation by Science and Technology (IWT) and Research Foundation-Flanders (FWO-V, of which Keyaerts M is a senior clinical investigator). YDV was supported by Kom op tegen Kanker and is currently funded via an FWO-SB fellowship.

Author contributions

CG contributed to the design of the study, performed and analyzed experiments and assisted in writing the manuscript. YDV: performed and analyzed experiments, and assisted in writing the manuscript. DE generated several of the lentiviral transfer vectors used in this manuscript, performed and analyzed experiments, and assisted in writing the manuscript. SL performed and analyzed experiments, and assisted in writing the manuscript. MK provided the in vivo bioluminescence imaging protocol and facility, and assisted in writing the manuscript. GR generated and characterized nanobody DC2.1 used in this study, and assisted in writing the manuscript. Karine Breckpot: contributed to the design of the study, performed and analyzed experiments, and assisted in writing of manuscript.

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Author notes

  1. C Goyvaerts and Y De Vlaeminck: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel (VUB), Brussels, Belgium

    C Goyvaerts, Y De Vlaeminck & K Breckpot

  2. Department of Immunomodulation, Navarrabiomed, Pamplona, Spain

    D Escors

  3. Hannover Medical School, ZTL Imaging-Center, Hannover, Germany

    S Lienenklaus

  4. In Vivo Cellular and Molecular Imaging Laboratory, VUB, Brussels, Belgium

    M Keyaerts

  5. Nuclear Medicine Department, UZ Brussel, Brussels, Belgium

    M Keyaerts

  6. Cellular and Molecular Immunology Laboratory VUB, Brussels, Belgium

    G Raes

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  1. C Goyvaerts
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Correspondence to K Breckpot.

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Goyvaerts, C., De Vlaeminck, Y., Escors, D. et al. 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 Ther 24, 370–375 (2017). https://doi.org/10.1038/gt.2017.30

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