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Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming

Nature Medicine 7, 297–303 (2001) | Download Citation

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Abstract

The initiation of T-cell–mediated antitumor immune responses requires the uptake and processing of tumor antigens by dendritic cells and their presentation on MHC-I molecules. Here we show in a human in vitro model system that exosomes, a population of small membrane vesicles secreted by living tumor cells, contain and transfer tumor antigens to dendritic cells. After mouse tumor exosome uptake, dendritic cells induce potent CD8+ T-cell–dependent antitumor effects on syngeneic and allogeneic established mouse tumors. Therefore, exosomes represent a novel source of tumor-rejection antigens for T-cell cross priming, relevant for immunointerventions.

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References

  1. 1.

    & Human tumor antigens recognized by T lymphocytes. J. Exp. Med. 183, 725–729 (1996).

  2. 2.

    A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 10, 281–287 (1999).

  3. 3.

    The makings of a tumor rejection antigen. Immunity 11, 263–270 (1999).

  4. 4.

    , , & Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochtonous host. Cancer Res. 20, 1561–1572 (1960).

  5. 5.

    , , & Antigenic properties of chemically induced tumors. Ann. NY Acad. Sci. 101, 80–106 (1962).

  6. 6.

    Cancer immunology, the search for specificity. Cancer Res. 41, 361–375 (1981).

  7. 7.

    et al. The shared tumor-specific antigen encoded by mouse gene P1A is a target not only for CTL but also for tumor rejection. Eur. J. Immunol. 28, 4010–4019 (1998).

  8. 8.

    et al. Multiple lineages of tumors express a common tumor antigen, P1A, but they are not cross-protected. J. Immunol. 155, 5323–5329 (1995).

  9. 9.

    & A natural cytotoxic T cell response in a spontaneously regressing human melanoma targets a neoantigen resulting from a somatic point mutation. Eur. J. Immunol. 29, 592–601 (1999).

  10. 10.

    et al. Major histocompatibility complex class I restricted cytotoxic T cells specific for natural melanoma peptides recognize unidentified shared melanoma antigens. Cancer Res. 59, 2287–2291 (1999).

  11. 11.

    et al. B7-CD28 costimulation unveils the hierarchy of tumor epitopes recognized by the majority of HLA-A2-restricted CD8+ CTL. J. Exp. Med. 183, 791–800 (1996).

  12. 12.

    , & Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392, 86–89 (1998).

  13. 13.

    et al. DC acquire the MAGE3 human tumor antigen from apoptotic cells and induce a class I-restricted T cell response. Proc. Natl. Acad. Sci. 97, 2185–2190 (2000).

  14. 14.

    , & Murine dendritic cells pulsed with whole tumor lysates mediate potent antitumor immune responses in vitro and in vivo. Proc. Natl. Acad. Sci. 95, 9482–9487 (1998).

  15. 15.

    , , & Heat shock proteins transfer peptides during antigen processing and CTL priming. Immunogenetics 39, 93–98 (1994).

  16. 16.

    , , , & Immunotherapy of tumors with autologous tumor derived heat shock protein preparations. Science 278, 117–120 (1997).

  17. 17.

    , , & Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J. Exp. Med. 184, 465–472 (1996).

  18. 18.

    et al. Induction of primary carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes in vitro using human dendritic cells transfected with RNA. Nature Biotechnol. 16, 364–369 (1998).

  19. 19.

    et al. B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med. 183, 1161–1172 (1996).

  20. 20.

    et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nature Med. 4, 594–600 (1998).

  21. 21.

    et al. Molecular characterization of dendritic cell-derived exosomes: selective accumulation of the heat shock protein hsc73. J. Cell Biol. 147, 599–610 (1999).

  22. 22.

    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. 32, 20121–20127 (1998).

  23. 23.

    & Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor α. J. Exp. Med. 179, 1109–1118 (1994).

  24. 24.

    et al. Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines. J. Exp. Med. 183, 87–97 (1996).

  25. 25.

    et al. Diversity of the cytotoxic melanoma-specific immune response: some CTL clones recognize autologous fresh tumor cells and not tumor cell lines. J. Immunol. 158, 3787–3795 (1997).

  26. 26.

    et al. Human renal cell carcinoma xenografts in SCID mice: tumorigenicity correlates with a poor clinical prognosis. Lab. Invest. 79, 879–888 (1999).

  27. 27.

    et al. Dendritic cells directly trigger NK cell functions: a cross-talk relevant in innate antitumor immune responses in vivo. Nature Med. 5, 405–411 (1999).

  28. 28.

    et al. BCR-ABL and constitutively active erythropoietin receptor (cEpoR) activate distinct mechanisms for growth factor-independence and inhibition of apoptosis in Ba/F3 cell line. Oncogene 16, 489–496 (1998).

  29. 29.

    , , , & Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature 312, 548–551 (1984).

  30. 30.

    et al. Accumulation of major histocompatibility complex class II molecules in mast cell secretory granules and their release upon degranulation. Mol. Biol. Cell 8, 2631–2645 (1997).

  31. 31.

    In Situ demonstration of renal-cell-carcinoma-specific T-cell clones. Int. J. Cancer 66, 564–570 (1996).

  32. 32.

    et al. Tumor immunogenicity determines the effect of B7 costimulation on T cell-mediated tumor immunity. J. Exp. Med. 179, 523–532 (1994).

  33. 33.

    et al. Direct vesicular transport of MHC class II molecules from lysosomal structures to the cell surface. J. Cell Biol. 135, 611–622 (1996).

  34. 34.

    et al. Recycling MHC class I molecules and endosomal peptide loading. Proc. Natl. Acad. Sci. 96, 10326–10331 (1999).

  35. 35.

    Cross-reacting tumor associated transplantation antigen on primary 3-methylcholanthrene-induced BALB/c sarcomas. Mol. Biother. 4, 223–228 (1989).

  36. 36.

    & Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 33, 967–977 (1983).

  37. 37.

    , , & Exosome formation during maturation of mammalian and avian reticulocytes: evidence that exosome release is a major route for externalization of obsolete membrane proteins. J. Cell Biol. 147, 27 (1991).

  38. 38.

    , , , & Exosomes released during reticulocyte maturation bind to fibronectin via α4β1. Eur. J. Biochem. 267, 583–590 (2000).

  39. 39.

    Immunotherapy with CTLs restricted by nonself MHC. Immunol. Today 20, 180–183 (1999).

  40. 40.

    , & The alphavbeta5 integrin recruits the Crk/Dock180 molecular complex for phagocytosis of apoptotic cells. Nature Cell Biol. 2, 899–905 (2000).

  41. 41.

    et al. Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J. Exp. Med. 191, 423–433 (2000).

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Acknowledgements

We thank F. André, A. Caignard and C. Bonnerot for helpful discussions; M.-F. Avril for providing us with melanoma patient-derived tumor material; A. Le Cesne for blood samples; S. Koscielny for statistical analysis; and the staff of the animal facility for animal care and handling. This work was supported by the Ligue Française de Lutte Contre le Cancer 'Axe Immunologie des Tumeurs', INSERM, CNRS, APCells SA and Inc., GEFLUC and Association pour la Recherche Contre Le Cancer ARC. J.W. was supported by Ligue Nationale de Lutte Contre le Cancer, A.L. by ARC.

Author information

    • Joseph Wolfers
    •  & Anne Lozier

    J.W. & A.L., contributed equally to this study.

Affiliations

  1. Immunology Unit, Department of Clinical Biology, Institut Gustave Roussy, Villejuif, France

    • Joseph Wolfers
    • , Anne Lozier
    • , Carole Masurier
    • , Caroline Flament
    • , Thomas Tursz
    • , Eric Angevin
    •  & Laurence Zitvogel

  2. Unité INSERM U520, Paris, France

    • Armelle Regnault
    • , Clotilde Théry
    • , Florence Faure
    •  & Sebastian Amigorena

  3. UMR 144 CNRS Institut Curie, Paris, France

    • Graça Raposo

  4. APCells SA, Institut Gustave Roussy, Villejuif, France

    • Stéphanie Pouzieux

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Correspondence to Sebastian Amigorena or Laurence Zitvogel.

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https://doi.org/10.1038/85438

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