Horm Metab Res 2008; 40(2): 82-88
DOI: 10.1055/s-2007-1022548
Review

© Georg Thieme Verlag KG Stuttgart · New York

Exosomes for the Treatment of Human Malignancies

S. Viaud 1 , E. Ullrich 1 , L. Zitvogel 1 , 2 , 3 , N. Chaput 1 , 2
  • 1Institut National de la Santé Et de la Recherche Médicale, INSERM U805, Institut Gustave Roussy, Villejuif, France
  • 2Centre d'investigation Clinique, CIC BT507, Institut Gustave Roussy, Villejuif, France
  • 3Faculté de Médecine Paris Sud, Université Paris XI
Further Information

Publication History

received 22.08.2007

accepted 15.10.2007

Publication Date:
19 February 2008 (online)

Abstract

Exosomes are nanometer particles (50-100 nm) secreted by most living cells. The first description of exosomes was made in 1987 by Rose Johnstone, who described a vesicle formation during the maturation process of reticulocytes. At this time it has been suggested that exosome release could represent a major route for the externalization of obsolete membrane proteins. A renewed vision of exosome function was raised when Graça Raposo demonstrated in 1996 that exosomes derived from B cells could have immunogenic capacities. Since then, exosomes have been described in numerous cell types in vitro, including hematopoietic and nonhematopoietic cells. The physiological relevance of exosomes in vivo still remains unclear. Studies have demonstrated that exosomes can play a role in the physiology of originating cells (i.e., reticulocyte-derived exosomes). Furthermore, exosomes can act on intercellular communication by allowing exchange of proteins, lipids, and also mRNA between cells. Finally, exosomes have been shown to modulate the immune system (i.e., dendritic cells, B cells, and tumor cells). In the present review, we have focused on the potential therapeutic role of exosomes as a cell free vaccine in cancer.

References

  • 1 Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes).  J Biol Chem. 1987;  262 9412-9420
  • 2 Johnstone RM, Bianchini A, Teng K. Reticulocyte maturation and exosome release: transferrin receptor containing exosomes shows multiple plasma membrane functions.  Blood. 1989;  74 1844-1851
  • 3 Thery C, Duban L, Segura E. et al . Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes.  Nature Immunol. 2002;  3 1156-1162
  • 4 Andre F, Chaput N, Schartz NE. et al . Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells.  J Immunol. 2004;  172 2126-2136
  • 5 Chaput N, Schartz NE, Andre F. et al . Exosomes as potent cell-free peptide-based vaccine. II. Exosomes in CpG adjuvants efficiently prime naive Tc1 lymphocytes leading to tumor rejection.  J Immunol. 2004;  172 2137-2146
  • 6 Hao S, Yuan J, Xiang J. Nonspecific CD4+ T cells with uptake of antigen-specific dendritic cell-released exosomes stimulate antigen-specific CD8+ CTL responses and long-term T cell memory.  J Leukoc Biol. 2007;  82 829-838
  • 7 Valadi H, Ekstrom K, Bossios A. et al . Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.  Nature Cell Biol. 2007;  9 654-659
  • 8 Denzer K, Kleijmeer MJ, Heijnen HF, Stoorvogel W, Geuze HJ. Exosome: from internal vesicle of the multivesicular body to intercellular signaling device.  J Cell Sci. 2000;  113 ((Pt 19)) 3365-3374
  • 9 Denzer K, Eijk M van, Kleijmeer MJ. et al . Follicular dendritic cells carry MHC class II-expressing microvesicles at their surface.  J Immunol. 2000;  165 1259-1265
  • 10 Quah B, O’Neill HC. Review: The application of dendritic cell-derived exosomes in tumour immunotherapy.  Cancer Biother Radiopharm. 2000;  15 185-194
  • 11 Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function.  Nature Rev. 2002;  2 569-579
  • 12 Raposo G, Nijman HW, Stoorvogel W. et al . B lymphocytes secrete antigen-presenting vesicles.  J Exp Med. 1996;  183 1161-1172
  • 13 Zitvogel L, Regnault A, Lozier A. et al . Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes.  Nature Med. 1998;  4 594-600
  • 14 Wolfers J, Lozier A, Raposo G. et al . Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming.  Nature Med. 2001;  7 297-303
  • 15 Escola JM, Kleijmeer MJ, Stoorvogel W. et al . Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes.  J Biol Chem. 1998;  273 20121-20127
  • 16 Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules.  Blood. 1999;  94 3791-3799
  • 17 Thery C, Regnault A, Garin J. et al . Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73.  J Cell Biol. 1999;  147 599-610
  • 18 Skokos D, Le Panse S, Villa I. et al . Mast cell-dependent B and T lymphocyte activation is mediated by the secretion of immunologically active exosomes.  J Immunol. 2001;  166 868-876
  • 19 Niel G van, Raposo G, Candalh C. et al . Intestinal epithelial cells secrete exosome-like vesicles.  Gastroenterology. 2001;  121 337-349
  • 20 Andre F, Schartz NE, Movassagh M. et al . Malignant effusions and immunogenic tumour-derived exosomes.  Lancet. 2002;  360 295-305
  • 21 Blanchard N, Lankar D, Faure F. et al . TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex.  J Immunol. 2002;  168 3235-3241
  • 22 Laulagnier K, Grand D, Dujardin A. et al . PLD2 is enriched on exosomes and its activity is correlated to the release of exosomes.  FEBS Lett. 2004;  572 11-14
  • 23 Savina A, Vidal M, Colombo MI. The exosome pathway in K562 cells is regulated by Rab11.  J Cell Sci. 2002;  115 2505-2515
  • 24 Amzallag N, Passer BJ, Allanic D. et al . TSAP6 facilitates the secretion of translationally controlled tumor protein/histamine-releasing factor via a nonclassical pathway.  J Biol Chem. 2004;  279 46104-46112
  • 25 Yu X, Harris SL, Levine AJ. The regulation of exosome secretion: a novel function of the p53 protein.  Cancer Res. 2006;  66 4795-4801
  • 26 Thery C, Boussac M, Veron P. et al . Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles.  J Immunol. 2001;  166 7309-7318
  • 27 Chaput N, Flament C, Viaud S. et al . Dendritic cell derived-exosomes: biology and clinical implementations.  J Leukoc Biol. 2006;  80 471-478
  • 28 Mignot G, Roux S, Thery C, Segura E, Zitvogel L. Prospects for exosomes in immunotherapy of cancer.  J Cell Mol Med. 2006;  10 376-388
  • 29 Wubbolts R, Leckie RS, Veenhuizen PT. et al . Proteomic and biochemical analyses of human B cell-derived exosomes. Potential implications for their function and multivesicular body formation.  J Biol Chem. 2003;  278 10963-10972
  • 30 Laulagnier K, Motta C, Hamdi S. et al . Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization.  The Biochem J. 2004;  380 161-171
  • 31 Lamparski HG, Metha-Damani A, Yao JY. et al . Production and characterization of clinical grade exosomes derived from dendritic cells.  J Immunol Meth. 2002;  270 211-226
  • 32 Pan BT, Johnstone RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor.  Cell. 1983;  33 967-978
  • 33 Harding C, Heuser J, Stahl P. Endocytosis and intracellular processing of transferrin and colloidal gold-transferrin in rat reticulocytes: demonstration of a pathway for receptor shedding.  Eur J Cell Biol. 1984;  35 256-263
  • 34 Rieu S, Geminard C, Rabesandratana H, Sainte-Marie J, Vidal M. Exosomes released during reticulocyte maturation bind to fibronectin via integrin alpha4beta1.  Eur J Biochem/FEBS. 2000;  267 583-590
  • 35 Clayton A, Turkes A, Dewitt S. et al . Adhesion and signaling by B cell-derived exosomes: the role of integrins.  FASEB J. 2004;  18 977-979
  • 36 Peters PJ, Borst J, Oorschot V. et al . Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes.  J Exp Med. 1991;  173 1099-1109
  • 37 Peters PJ, Geuze HJ, Donk HA Van der. et al . Molecules relevant for T cell-target cell interaction are present in cytolytic granules of human T lymphocytes.  Eur J Immunol. 1989;  19 1469-1475
  • 38 Raposo G, Tenza D, Mecheri S. et al . Accumulation of major histocompatibility complex class II molecules in mast cell secretory granules and their release upon degranulation.  Mol Biol Cell. 1997;  8 2631-2645
  • 39 Skokos D, Botros HG, Demeure C. et al . Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo.  J Immunol. 2003;  170 3037-3045
  • 40 Karlsson M, Lundin S, Dahlgren U. et al . “Tolerosomes” are produced by intestinal epithelial cells.  Eur J Immunol. 2001;  31 2892-2900
  • 41 Niel G van, Heyman M. The epithelial cell cytoskeleton and intracellular trafficking. II. Intestinal epithelial cell exosomes: perspectives on their structure and function.  Am J Physiol Gastrointest Liver Physiol. 2002;  283 G251-G255
  • 42 Niel G Van, Mallegol J, Bevilacqua C. et al . Intestinal epithelial exosomes carry MHC class II/peptides able to inform the immune system in mice.  Gut. 2003;  52 1690-1697
  • 43 Janiszewski M, Do Carmo AO, Pedro MA. et al . Platelet-derived exosomes of septic individuals possess proapoptotic NAD(P)H oxidase activity: A novel vascular redox pathway.  Critical Care Med. 2004;  32 818-825
  • 44 Robertson C, Booth SA, Beniac DR. et al . Cellular prion protein is released on exosomes from activated platelets.  Blood. 2006;  107 3907-3911
  • 45 Riteau B, Faure F, Menier C. et al . Exosomes bearing HLA-G are released by melanoma cells.  Human Immunol. 2003;  64 1064-1072
  • 46 Altieri SL, Khan AN, Tomasi TB. Exosomes from plasmacytoma cells as a tumor vaccine.  J Immunother 1997. 2004;  27 282-288
  • 47 Hegmans JP, Bard MP, Hemmes A. et al . Proteomic analysis of exosomes secreted by human mesothelioma cells.  Am J Pathol. 2004;  164 1807-1815
  • 48 Andreola G, Rivoltini L, Castelli C. et al . Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles.  J Exp Med. 2002;  195 1303-1316
  • 49 Huber V, Fais S, Iero M. et al . Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape.  Gastroenterology. 2005;  128 1796-1804
  • 50 Valenti R, Huber V, Filipazzi P. et al . Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes.  Cancer Res. 2006;  66 9290-9298
  • 51 Liu C, Yu S, Zinn K. et al . Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function.  J Immunol. 2006;  176 1375-1385
  • 52 Clayton A, Mitchell JP, Court J, Mason MD, Tabi Z. Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2.  Cancer Res. 2007;  67 7458-7466
  • 53 Hsu DH, Paz P, Villaflor G. et al . Exosomes as a tumor vaccine: enhancing potency through direct loading of antigenic peptides.  J Immunother 1997. 2003;  26 440-450
  • 54 Curiel TJ, Coukos G, Zou L. et al . Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.  Nature Med. 2004;  10 942-949
  • 55 Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses.  Annu Rev Immunol. 2004;  22 531-562
  • 56 Viguier M, Lemaitre F, Verola O. et al . Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells.  J Immunol. 2004;  173 1444-1453
  • 57 Ghiringhelli F, Larmonier N, Schmitt E. et al . CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative.  Eur J Immunol. 2004;  34 336-344
  • 58 Ghiringhelli F, Menard C, Puig PE. et al . Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.  Cancer Immunol Immunother. 2007;  56 641-648
  • 59 Taieb J, Chaput N, Schartz N. et al . Chemoimmunotherapy of tumors: cyclophosphamide synergizes with exosome based vaccines.  J Immunol. 2006;  176 2722-2729
  • 60 Segura E, Amigorena S, Thery C. Mature dendritic cells secrete exosomes with strong ability to induce antigen-specific effector immune responses.  Blood Cells Mol Dis. 2005;  35 89-93
  • 61 Segura E, Nicco C, Lombard B. et al . ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming.  Blood. 2005;  106 216-223
  • 62 Sprent J. Direct stimulation of naive T cells by antigen-presenting cell vesicles.  Blood Cells Mol Dis. 2005;  35 17-20
  • 63 Escudier B, Dorval T, Chaput N. et al . Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial.  Journal of translational medicine [electronic resource]. 2005;  3 10
  • 64 Peche H, Heslan M, Usal C, Amigorena S, Cuturi MC. Presentation of donor major histocompatibility complex antigens by bone marrow dendritic cell-derived exosomes modulates allograft rejection.  Transplantation. 2003;  76 1503-1510
  • 65 Kim SH, Lechman ER, Bianco N. et al . Exosomes derived from IL-10-treated dendritic cells can suppress inflammation and collagen-induced arthritis.  J Immunol. 2005;  174 6440-6448
  • 66 Kim SH, Bianco N, Menon R. et al . Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive.  Mol Ther. 2006;  13 289-300
  • 67 Abusamra AJ, Zhong Z, Zheng X. et al . Tumor exosomes expressing Fas ligand mediate CD8+ T-cell apoptosis.  Blood Cells Mol Dis. 2005;  35 169-173
  • 68 Valenti R, Huber V, Iero M. et al . Tumor-released microvesicles as vehicles of immunosuppression.  Cancer Res. 2007;  67 2912-2915
  • 69 Clayton A, Tabi Z. Exosomes and the MICA-NKG2D system in cancer.  Blood Cells Mol Dis. 2005;  34 206-213
  • 70 Dai S, Wan T, Wang B. et al . More efficient induction of HLA-A*0201-restricted and carcinoembryonic antigen (CEA)-specific CTL response by immunization with exosomes prepared from heat-stressed CEA-positive tumor cells.  Clin Cancer Res. 2005;  11 7554-7563
  • 71 Aline F, Bout D, Amigorena S, Roingeard P, Dimier-Poisson I. Toxoplasma gondii antigen-pulsed-dendritic cell-derived exosomes induce a protective immune response against T. gondii infection.  Infect Immun. 2004;  72 4127-4137
  • 72 Colino J, Snapper CM. Exosomes from bone marrow dendritic cells pulsed with diphtheria toxoid preferentially induce type 1 antigen-specific IgG responses in naive recipients in the absence of free antigen.  J Immunol. 2006;  177 3757-3762
  • 73 Colino J, Snapper CM. Dendritic cell-derived exosomes express a Streptococcus pneumoniae capsular polysaccharide type 14 cross-reactive antigen that induces protective immunoglobulin responses against pneumococcal infection in mice.  Infect Immun. 2007;  75 220-230
  • 74 Kuate S, Cinatl J, Doerr HW, Uberla K. Exosomal vaccines containing the S protein of the SARS coronavirus induce high levels of neutralizing antibodies.  Virology. 2007;  362 26-37

Correspondence

N. ChaputPharm D, PhD 

Centre d'investigation clinique

CIC BT507

Institut Gustave Roussy

39 rue Camille Desmoulins

94805 Villejuif

France

Phone: +33/1/42 11 66 16

Fax: +33/1/42 11 60 94

Email: nathalie.chaput@igr.fr

    >