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Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow

Nature Medicine volume 7, pages 452–458 (2001)Cite this article

Abstract

In an analysis of 84 primary-operated breast cancer patients and 11 healthy donors, we found that the bone marrow of most patients contained memory T cells with specificity for tumor-associated antigens. Patients' bone marrow and peripheral blood contained CD8+ T cells that specifically bound HLA/peptide tetramers. In short-term culture with autologous dendritic cells pre-pulsed with tumor lysates, patients' memory T cells from bone marrow (but not peripheral blood) could be specifically reactivated to interferon-γ–producing and cytotoxic effector cells. A single transfer of restimulated bone-marrow T cells into NOD/SCID mice caused regression of autologous tumor xenotransplants associated with infiltration by human T cells and tumor-cell apoptosis and necrosis. T cells from peripheral blood showed much lower anti-tumor reactivity. Our findings reveal an innate, specific recognition of breast cancer antigens and point to a possible novel cancer therapy using patients' bone-marrow–derived memory T cells.

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Figure 1: Analysis of tumor reactive memory T cells by ELISPOT.
Figure 2: Cytotoxic anti-tumor reactivity of bone-marrow and peripheral-blood T cells.
Figure 3: Tumor-peptide–specific CD8+ T cells in bone marrow and peripheral blood.
Figure 4: Tumor-peptide–specific cytotoxicity of bone-marrow and peripheral-blood T cells.
Figure 5: Human tumor regression in NOD/SCID mice treated with patient-derived T cells.
Figure 6: T-cell infiltration and destruction of tumor transplants in treated mice.

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References

  1. Lanzavecchia, A. & Sallusto, F. From synapses to immunological memory: the role of sustained T cell stimulation. Curr. Opin. Immunol. 12, 92–98 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Goldrath, A.W. & Bevan, M.J. Selecting and maintaining a diverse T-cell repertoire. Nature (Lond.). 402, 255–262 (1999).

    Article  CAS  Google Scholar 

  3. Zinkernagel, R.M. et al. On immunological memory. Annu. Rev. Immunol. 14, 333–367 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Sallusto, F., Lenig, D., Förster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 402, 708–712 (1999).

    Article  Google Scholar 

  5. Hamann, D. et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J. Exp. Med. 186, 1407–1418 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Veiga-Fernandes, H., Walter, U., Bourgeois, C., McLean, A. & Rocha, B. Response of naive and memory CD8+ T cells to antigen stimulation in vivo. Nature Immunol. 1, 47–53 (2000).

    Article  CAS  Google Scholar 

  7. Sprent, J., Tough, D.F. & Sun, S. Factors controlling the turnover of T memory cells. Immunol. Rev. 156, 79–85 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Tanchot, C., Lemonnier, F.A., Perarnau, B., Freitas, A.A. & Rocha, B. Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science 276, 2057–2062 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Garcia, S., DiSanto, J. & Stockinger, B. Following the development of a CD4 T cell immune response in vivo: from activation to memory formation. Immunity 11, 163–171 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Khazaie, K. et al. Persistence of dormant tumor cells in the bone marrow of tumor cell-vaccinated mice correlates with long-term immunological protection. Proc. Natl. Acad. Sci. USA 91, 7430–7434 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Müller, M. et al. Eb-lacZ tumor dormancy in bone marrow and lymph nodes: active control of proliferating tumor cells by CD8+ immune T cells. Cancer Res. 58, 5439–5446 (1998).

    PubMed  Google Scholar 

  12. Pantel, K., Cote, R.J. & Fodstad, O. Detection and clinical importance of micrometastatic disease. J. Natl. Cancer Inst. 91, 1113–1124 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Feuerer, M. et al. Enrichment of memory T cells and other profound immunological changes in the bone marrow from untreated breast cancer patients. Int. J. Cancer 92, 96–105 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Fisk, B., Blevins, T.L., Wharton, J.T. & Ioannides, C.G. Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines. J. Exp. Med. 181, 2109–2117 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Brossart, P. et al. Identification of HLA-A2-restricted T-cell epitopes derived from MUC1 tumor antigen for broadly applicable vaccine therapies. Blood 93, 4309–4317 (1999).

    CAS  PubMed  Google Scholar 

  16. Tsomides, T.J. et al. Naturally processed viral peptides recognized by cytotoxic T lymphocytes on cells chronically infected by human immunodeficiency virus type 1. J. Exp. Med. 180, 1283–1293 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Schultz, L.D. et al. Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J. Immunol. 154, 180–191 (1995).

    Google Scholar 

  18. Visonneau, S. Cesano, A., Torosian, M.H., Miller, E.J. & Santoli, D. Growth characteristics and metastatic properties of human breast cancer xenografts in immunodeficient mice. Am. J. Pathol. 152, 1299–1311 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Slavin, S. et al. Allogeneic cell therapy with donor peripheral blood cells and recombinant human interleukin-2 to treat leukemia relapse post allogeneic bone marrow transplantation. Blood 87, 2195–2204 (1996).

    CAS  PubMed  Google Scholar 

  20. Rosenberg, S.A. et al. Prospective randomized trial of high-dose interleukin-2 alone or in conjuction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J. Natl. Cancer Inst. 85, 622–632 (1993).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Schirrmacher, V., Schild, H.J., Gückel, B. & von Hoegen, P. Tumor specific CTL response requiring interactions of four different cell types and dual recognition of MHC class I and class II restricted tumor antigens. Immunol. Cell Biol. 71, 311–326 (1992).

    Article  Google Scholar 

  23. Singh-Jasuja, H. et al. The heat shock protein gp96 induces maturation of dendritic cells and down-regulation of ist receptor. Eur. J. Immunol. 30, 2211–2215 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Sauter, B. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gilboa, E. The making of a tumor rejection antigen. Immunity 11, 263–270 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Finn, O.J. et al. MUC1 epithelial tumor-mucin-based immunity and cancer vaccines. Immunol.Rev. 145, 61–89 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Disis, M.L., Grabstein, K.H., Sleath, D.R. & Cheever, M.A. Generation of immunity to the HER-2/neu oncogenic protein in patients with breast and ovarian cancer using a peptide–based vaccine. Clin. Cancer Res. 5, 1289–1297 (1999).

    CAS  PubMed  Google Scholar 

  28. Fields, R.C., Shimizu, K. & Mule, J.J. Murine dendritic cells pulsed with whole tumor lysates mediate potent antitumor immune responses in vitro and in vivo. Proc. Natl. Acad. Sci. USA 96, 8639–8644 (1999).

    Article  Google Scholar 

  29. Müerköster, S. et al. Graft-versus-Leukemia reactivity involves cluster formation between superantigen-reactive donor T lymphocytes and host macrophages. Clin. Cancer Res. 4, 3095–3106 (1998).

    PubMed  Google Scholar 

  30. Lee, P.D. et al. Charcterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nature Med. 5, 677–685 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Valmori, D. et al. Naturally occuring human lymphocyte antigen-A2 restricted CD8+ T-cell response to the cancer testis antigen NY-ESO-1 in melanoma patients. Cancer Res. 60, 4499–4506 (2000).

    CAS  PubMed  Google Scholar 

  32. Paramithiotis, E. & Cooper, M.D. Memory B lymphocytes migrate to bone marrow in humans. Proc. Natl. Acad. Sci. USA 94, 208–212 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Slifka, M.K., Whitmire, J.K. & Ahmed, R. Bone marrow contains virus-specific cytotoxic T lymphocytes. Blood 90, 2103–2108 (1997).

    CAS  PubMed  Google Scholar 

  34. Price, P.W. & Cerny, J. Characterization of CD4+ T cells in mouse bone marrow. I. Increased activated/memory phenotype and altered TCR V-β repertoire. Eur. J. Immunol. 29, 1051–1056 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Kuroda, M.J. et al. Simian immunodeficiency virus-specific cytotoxic T lymphocytes and cell-associated viral RNA levels in distinct lymphoid compartments of SIVmac-infected rhesus monkeys. Blood 96, 1474–1479 (2000).

    CAS  PubMed  Google Scholar 

  36. Papayannopoulou, T., Craddock, C., Nakamoto, B., Priestley, G.V. & Wolf, N.S. The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen. Proc. Natl. Acad. Sci. USA 92, 9647–9651 (1997).

    Article  Google Scholar 

  37. Briskin, M.J. et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am. J. Pathol. 151, 97–110 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Berlin, C. et al. α4β7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 74, 185–195 (1993).

    Article  CAS  PubMed  Google Scholar 

  39. Erle, D.J. et al. Expression and function of the MAdCAM-1 receptor, integrin α4β7, on human leucocytes. J. Immunol. 153, 517–528.

  40. Nestle, F.O. et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nature Med. 4, 328–332 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Kugler, A. et al. Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids. Nature Med. 6, 332–336 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Diel, K.J. et al. Micrometastatic breast cancer cells in bone marrow at primary surgery - prognostic value in comparison to nodal status. J. Natl. Cancer Inst. 88, 1652–1658 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Schuler, G. et al. in Dendritic cells (eds. Lotze, M.T. & Thomson, A.W.) 515–534 (Academic Press, San Diego, California, 1999).

    Google Scholar 

  44. Lalvani, A. et al. Rapid effector function in CD8+ memory T cells. J. Exp. Med. 186, 859–865 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Brossart, P. & Bevan, M.J. Selective activation of Fas/FasL mediated cytotoxicity by a self-peptide. J. Exp. Med. 183, 2449–2458 (1996).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This article is based on a PhD study by Markus Feuerer, University Heidelberg. We thank M. Rocha for initial help with establishing the clinical contact and the ELISPOT assay; J. Heep for providing some clinical samples; B. Kyewski for comments on the manuscript; G. Moldenhauer for human and mouse immunoglobulins and antibodies against HLA class I and HLA class II; S. Kaul for mAbs to human MUC1; A. Benner for help with statistics; J. Foerster, M. Bucur and M. Gehring for excellent technical assistance. We thank the NIAID Tetramer Facility and NIH AIDS Research and Reference Reagent Program (Bethesda, MD) for providing HLA-A2/peptide tetrameric complexes and the D. Hopp-Stiftung (Walldorf) and the M. Scheel-Stiftung (no. 10-1589-Schi5) for financial support.

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Author notes

  1. Markus Feuerer and Philipp Beckhove: M.F. and P.B. contributed equally to this study.

Authors and Affiliations

  1. Division of Cellular Immunology, Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany

    Markus Feuerer, Philipp Beckhove, Lianhua Bai, Volker Schirrmacher & Victor Umansky

  2. Department of Obstetrics and Gynecology, University Hospital, Heidelberg, Germany

    Erich-Franz Solomayer, Gunther Bastert & Ingo J. Diel

  3. Department of Obstetrics and Gynecology, University Hospital, Giessen, Germany

    Claudia Pedain

  4. St. Joseph's Hospital, Heidelberg, Germany

    Michael Oberniedermayr

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Feuerer, M., Beckhove, P., Bai, L. et al. Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow. Nat Med 7, 452–458 (2001). https://doi.org/10.1038/86523

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