Abstract
We have reported that retroviral particles adhered to the surface of antigen-specific T cells can be carried to metastases following adoptive transfer in vivo, a process we have called viral hitch hiking. Following antigen-driven T-cell accumulation at tumors, viral particles productively infect tumor cells via envelope/receptor dependent interactions (‘hand on’ of virus from the T cell to the tumor cell). We describe here a second envelope/receptor independent pathway of viral hand on from T cells, dependent on T-cell activation. We show that the endosomolytic property of perforin promotes release of viral particles from endosomes into which they are co-delivered along with cytotoxic granules from the activated T cell. Therefore, hand on of MLV particles lacking any envelope can be used for in vivo delivery of vectors, where targeting is at the extremely specific level of recognition of antigen by the T-cell receptor, thereby dispensing with the need to engineer viral envelopes. These data reveal a novel pathway by which MLV viral particles exploit a functiol immunological synapse and present new opportunities both to improve the efficacy of adoptive T-cell transfer and to target vectors for systemic gene delivery.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Pizzato M, Marlow SA, Blair ED, Takeuchi Y . Initial binding of murine leukemia virus particles to cells does not require specific Env-receptor interaction. J Virol 1999; 73: 8599–8611.
Pizzato M, Blair ED, Fling M, Kopf J, Tomassetti A, Weiss RA et al. Evidence for nonspecific adsorption of targeted retrovirus vector particles to cells. Gene Therapy 2001; 8: 1088–1096.
Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC, Middel J et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 2000; 100: 587–597.
Bobardt MD, Saphire AC, Hung HC, Yu X, Van der Schueren B, Zhang Z et al. Syndecan captures, protects, and transmits HIV to T lymphocytes. Immunity 2003; 18: 27–39.
Blomer U, Gruh I, Witschel H, Haverich A, Martin U . Shuttle of lentiviral vectors via transplanted cells in vivo. Gene Therapy 2005; 12: 67–74.
Harrington KJ, Alvarez-Vallina L, Crittenden M, Gough M, Chong H, Diaz RM et al. Cells as vehicles for cancer gene therapy: the missing link between targeted vectors and systemic delivery. Hum Gene Ther 2002; 13: 1263–1280.
Chester J, Ruchatz A, Gough M, Crittenden M, Chong H, Loic-Cosset F et al. Tumor antigen-specific induction of transcriptionally targeted retroviral vectors from chimeric immune receptor-modified T cells. Nat Biotechnol 2002; 20: 256–263.
Crittenden M, Gough M, Chester J, Kottke T, Thompson J, Ruchatz A et al. Pharmacologically regulated production of targeted retrovirus from T cells for systemic anti-tumor gene therapy. Cancer Res 2003; 63: 3178–3180.
Harrington KJ, Linardakis E, Vile RG . Transcriptional control: an essential component of cancer gene therapy strategies? Adv Drug Delivery Rev 2000; 44: 167–184.
Cole C, Qiao J, Kottke T, Diaz RM, Sanchez-Perez L, Blum G et al. Systemic delivery of therapeutic viral vectors using hitch hiking on antigen specific T cells. Nat Med 2005; 11: 1073–1081.
Rosenberg SA, Dudley ME . Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes. Proc Natl Acad Sci USA 2004; 101 (Suppl 2): 14639–14645.
Dudley ME, Rosenberg SA . Adoptive-Cell-Transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 2003; 3: 666–676.
Yee C, Riddell SR, Greenberg PD . In vivo tracking of tumor-specific T cells. Curr Opin Immunol 2001; 13: 141–146.
Yee C, Thompson JA, Roche P, Byrd DR, Lee PP, Piepkorn M et al. Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of T cell-mediated vitiligo. J Exp Med 2000; 192: 1637–1644.
Dudley ME, Wunderlich J, Nishimura MI, Yu D, Yang JC, Topalian SL et al. Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J Immunother 2001; 24: 363–373.
Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002; 298: 850–854.
Palmer D, Balasubramaniam S, Hanada K, Wrzesinski C, Yu Z, Farid S et al. Vaccine-stimulated, adoptively transferred CD8+ T cells traffic indiscriminately and ubiquitously while mediating specific tumor destruction. J Immunol 2004; 15: 7209–7216.
Hogquist KA, Jameson SC, Health WR, Howard JL, Bevan MJ, Carbone FR . T cell receptor antagonistic peptides induce positive selection. Cell 1994; 76: 17.
Liebermann J . The ABCs of granule-mediated cytotoxicity: new weapons in the Arsenal. Nat Rev Immunol 2003; 3: 361–370.
Bots M, Kolfscoten IGM, Bres S, Rademaker MTGA, de Roo GM, Kruse M et al. SPI-CI and SPI-6 cooperate in the protection from effector cell-mediated cytotoxicity. Blood 2005; 105: 1153–1161.
Froelich CJ, Orth K, Turbov J, Seth P, Gottlieb R, Babior B et al. New paradigm for lymphocyte granule-mediated cytotoxicity. Target cells bind and internalize granzyme B, but an endosomolytic agent is necessary for cytosolic delivery and subsequent apoptosis. J Biol Chem 1996; 271: 29073–29079.
Browne KA, Blink E, Sutton VR, Froelich CJ, Jans DA, Trapani JA . Cytosolic delivery of granzyme B by bacterial toxins: evidence that endosomal disruption, in addition to transmembrane pore formation, is an important function of perforin. Mol Cell Biol 1999; 19: 8604–8615.
Kurschus FC, Bruno R, Fellows E, Falk CS, Jenne DE . Membrane receptors are not required to deliver granzyme B during killer cell attack. Blood 2005; 105: 2049–2058.
Raja SM, Metkar SS, Froelich CJ . Cytotoxic granule-mediated apoptosis: unraveling the complex mechanism. Curr Opin Immunol 2003; 15: 528–532.
Igakura T, Stinchcombe JC, Goon PK, Taylor GP, Weber JN, Griffiths GM et al. Spread of HTLV-I between lymphocytes by virus induced polarisation of the cytoskeleton. Science 2003; 299: 1670–1671.
Jolly C, Kashefi K, Hollinshead M, Sattentau QJ . HIV-1 cell transfer across an env-induced, actin dependent synapse. J Exp Med 2004; 19: 283–293.
Sandrin V, Russell SJ, Cosset FL . Targeting retroviral and lentiviral vectors. Curr Top Microbiol and Immunol 2003; 281: 137–178.
Weiss RA, Chetankuma ST . Retrovirus receptors. Cell 1995; 82: 531–533.
Linardakis E, Bateman A, Phan V, Ahmed A, Gough M, Olivier K et al. Enhancing the efficacy of a weak allogeneic melanoma vaccine by viral fusogenic membrane glycoprotein-mediated tumor cell-tumor cell fusion. Cancer Res 2002; 62: 5495–5504.
Miller AD, Garcia JV, Von Suhr N, Lynch CM, Wilson C, Eiden MV . Construction and properties of retroviral packaging cells based on gibbon ape leukemia virus. J Virol 1991; 65: 2220–2224.
Grossman WJ, Verbsky JW, Tollefsen BL, Kemper C, Atkinson JP, Ley TJ . Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood 2004; 104: 2840–2848.
Kolokoltsov AA, Davey RA . Rapid and sensitive detection of retrovirus entry by using a novel luciferase-based content mixing assay. J Virol 2004; 78: 5124–5132.
Wagner RR, Rose JK In: Fields BN, Knupe DM, Howley PM (eds). Fundamental Virology. Lippincott-Raven Publishers: Philadelphia, 1996, pp 561–575.
Chong H, Todryk S, Hutchinson G, Hart IR, Vile RG . Tumour cell expression of B7 costimulatory molecules and interleukin-12 or granulocyte–macrophage colony stimulating factor induces a local antitumour response and may generate systemic protective immunity. Gene Therapy 1998; 5: 223–232.
Morgenstern JP, Land H . Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res 1990; 18: 3587–3596.
Diaz RM, Eisen T, Hart IR, Vile RG . Exchange of viral promoter/enhancer elements with heterologous regulatory sequences generates targeted hybrid long terminal repeat vectors for gene therapy of melanoma. J Virol 1998; 72: 789–795.
Wagner MJ, Sharp JA, Summers WC . Nucleotide sequence of the thymidine kinase gene of herpes simplex virus type 1. Proc Natl Acad Sci USA 1981; 78: 1441–1445.
Markowitz D, Goff S, Bank A . Construction and use of a safe and efficient amphotropic packaging cell line. Virology 1988; 167: 400–406.
Burns JC, Friedmann T, Driever W, Burrascano M, Yee JK . Vesicular stomatitis virus G glycoprotein pseudotyped retroviral vectors: concentration to very high titer and efficient gene transfer into mammalian and nonmammalian cells. Proc Natl Acad Sci USA 1993; 90: 8033–8037.
Daniels G, Sanchez-Perez L, Kottke T, Diaz RM, Thompson J, Lai M et al. A simple method to cure established tumors by inflammatory killing of normal cells. Nat Biotechnol 2004; 22: 1125–1132.
Altman DG (ed). Analysis of survival times. In Practical Statistics for Medical Research. London: Chapman and Hall, 1991, pp 365–395.
Acknowledgements
We thank Toni L Higgins for expert secretarial assistance. This work was supported by the Mayo Foundation and by NIH Grants 1RO1CA94180 and 1RO1CA107082.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kottke, T., Qiao, J., Diaz, R. et al. The perforin-dependent immunological synapse allows T-cell activation-dependent tumor targeting by MLV vector particles. Gene Ther 13, 1166–1177 (2006). https://doi.org/10.1038/sj.gt.3302722
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3302722
Keywords
This article is cited by
-
Ad5/3 is able to avoid neutralization by binding to erythrocytes and lymphocytes
Cancer Gene Therapy (2021)
-
Antitumor efficacy of oncolytic herpes simplex virus adsorbed onto antigen-specific lymphocytes
Cancer Gene Therapy (2012)
-
Cell Carriers for Oncolytic Viruses: Fed Ex for Cancer Therapy
Molecular Therapy (2009)
-
Augmented transgene expression in transformed cells using a parvoviral hybrid vector
Cancer Gene Therapy (2008)
-
Loading of oncolytic vesicular stomatitis virus onto antigen-specific T cells enhances the efficacy of adoptive T-cell therapy of tumors
Gene Therapy (2008)