Cancer and Metastasis Reviews

, Volume 33, Issue 1, pp 309–320 | Cite as

Adoptive immunotherapy of metastatic breast cancer: present and future

  • Stefan Stefanovic
  • Florian Schuetz
  • Christof Sohn
  • Philipp Beckhove
  • Christoph Domschke


Breast cancer is a systemic disease with a primarily local component. Besides surgical resection and irradiation of the locoregional tumor setting, central therapeutic aim is the elimination of disseminated micrometastatic tumor cells using cytostatic and/or hormonal treatment. Nevertheless, in the course of time a majority of patients suffer from systemic recurrence in the form of distant metastases. Intriguingly, in this connection, intratumoral cytotoxic T lymphocytes might serve as independent predictors of treatment efficacy and clinical outcome. Loss of immune balance (tumor dormancy) during intensive cross talk between T cells and tumor cells in the bone marrow microenvironment is suggested one reason for distant metastatic relapse. In this clinical context, further supportive therapies become increasingly attractive, taking immunological features of breast cancer cells into special account. The present review aims to dissect bone marrow-derived cellular antitumor immune responses and translational immunologic treatment options regarding their actual relevance to patients’ clinical benefit and their future directions in breast cancer management.


Breast cancer T cell immunity Adoptive immunotherapy Tumor immune escape Immunomodulation 


  1. 1.
    Demicheli, R. (2001). Tumour dormancy: findings and hypotheses from clinical research on breast cancer. Seminars in Cancer Biology, 11(4), 297–306.PubMedGoogle Scholar
  2. 2.
    Mansi, J. L., Gogas, H., Bliss, J. M., Gazet, J. C., Berger, U., & Coombes, R. C. (1999). Outcome of primary-breast-cancer patients with micrometastases: a long-term follow-up study. Lancet, 354(9174), 197–202.PubMedGoogle Scholar
  3. 3.
    Cote, R. J., Rosen, P. P., Lesser, M. L., Old, L. J., & Osborne, M. P. (1991). Prediction of early relapse in patients with operable breast cancer by detection of occult bone marrow micrometastases. Journal of Clinical Oncology, 9(10), 1749–1756.PubMedGoogle Scholar
  4. 4.
    Braun, S., & Naume, B. (2005). Circulating and disseminated tumor cells. Journal of Clinical Oncology, 23(8), 1623–1626.PubMedGoogle Scholar
  5. 5.
    Braun, S., Vogl, F. D., Naume, B., Janni, W., Osborne, M. P., Coombes, R. C., et al. (2005). A pooled analysis of bone marrow micrometastasis in breast cancer. The New England Journal of Medicine, 353(8), 793–802.PubMedGoogle Scholar
  6. 6.
    Diel, I. J., Kaufmann, M., Costa, S. D., Holle, R., Von Minckwitz, G., Solomayer, E. F., et al. (1996). Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status. Journal of the National Cancer Institute, 88(22), 1652–1658.PubMedGoogle Scholar
  7. 7.
    Domschke, C., Neubrech, F., Dick, M., Rom, J., Beckhove, P., Sohn, C., et al. (2011). Intraoperative bone marrow puncture in breast cancer patients: prospective assessment of adverse side-effects. Breast, 20(1), 62–65.PubMedGoogle Scholar
  8. 8.
    Domschke, C., Diel, I. J., Englert, S., Kalteisen, S., Mayer, L., Rom, J., et al. (2012). Prognostic value of disseminated tumor cells in the bone marrow of patients with operable primary breast cancer: a long-term follow-up study. Annals of Surgical Oncology, 20(6), 1865–1871.PubMedGoogle Scholar
  9. 9.
    Pagès, F., Galon, J., Dieu-Nosjean, M.-C., Tartour, E., Sautès-Fridman, C., & Fridman, W.-H. (2010). Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene, 29(8), 1093–1102.PubMedGoogle Scholar
  10. 10.
    Calabrò, A., Beissbarth, T., Kuner, R., Stojanov, M., Benner, A., Asslaber, M., et al. (2009). Effects of infiltrating lymphocytes and estrogen receptor on gene expression and prognosis in breast cancer. Breast Cancer Research and Treatment, 116(1), 69–77.PubMedGoogle Scholar
  11. 11.
    Rody, A., Holtrich, U., Pusztai, L., Liedtke, C., Gaetje, R., Ruckhaeberle, E., et al. (2009). T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Research, 11(2), R15.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Mahmoud, S. M., Paish, E. C., Powe, D. G., Macmillan, R. D., Grainge, M. J., Lee, A. H., et al. (2011). Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. Journal of Clinical Oncology, 29(15), 1949–1955.PubMedGoogle Scholar
  13. 13.
    Liu, S., Lachapelle, J., Leung, S., Gao, D., Foulkes, W. D., & Nielsen, T. O. (2012). CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Research, 14(2), R48.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Yan, M., Jene, N., Byrne, D., Millar, E. K. A., O’Toole, S. A., McNeil, C. M., et al. (2011). Recruitment of regulatory T cells is correlated with hypoxia-induced CXCR4 expression, and is associated with poor prognosis in basal-like breast cancers. Breast Cancer Research, 13(2), R47.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Mahmoud, S. M. A., Paish, E. C., Powe, D. G., Macmillan, R. D., Lee, A. H. S., Ellis, I. O., et al. (2011). An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer. Breast Cancer Research and Treatment, 127(1), 99–108.PubMedGoogle Scholar
  16. 16.
    Liu, F., Lang, R., Zhao, J., Zhang, X., Pringle, G. A., Fan, Y., et al. (2011). CD8+ cytotoxic T cell and FOXP3+ regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Research and Treatment, 130(2), 645–655.PubMedGoogle Scholar
  17. 17.
    De Leeuw, R. J., Kost, S. E., Kakal, J. A., & Nelson, B. H. (2012). The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clinical Cancer Research, 18(11), 3022–3029.Google Scholar
  18. 18.
    Liu, F., Li, Y., Ren, M., Zhang, X., Guo, X., Lang, R., et al. (2012). Peritumoral FOXP3+ regulatory T cell is sensitive to chemotherapy while intratumoral FOXP3+ regulatory T cell is prognostic predictor of breast cancer patients. Breast Cancer Research and Treatment, 135(2), 459–467.PubMedGoogle Scholar
  19. 19.
    Ma, C., Zhang, Q., Ye, J., Wang, F., Zhang, Y., Wevers, E., et al. (2012). Tumor-infiltrating γδ T lymphocytes predict clinical outcome in human breast cancer. Journal of Immunology, 189(10), 5029–5036.Google Scholar
  20. 20.
    Ye, J., Ma, C., Wang, F., Hsueh, E. C., Toth, K., Huang, Y., et al. (2013). Specific recruitment of γδ regulatory T cells in human breast cancer. Cancer Research, 73(20), 6137–6148.Google Scholar
  21. 21.
    Bos, R., & Sherman, L. A. (2010). CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes. Cancer Research, 70(21), 8368–8377.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Bos, R., Marquardt, K. L., Cheung, J., & Sherman, L. A. (2012). Functional differences between low- and high-affinity CD8(+) T cells in the tumor environment. Oncoimmunology, 1(8), 1239–1247.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Gu-Trantien, C., Loi, S., Garaud, S., Equeter, C., Libin, M., De Wind, A., et al. (2013). CD4+ follicular helper T cell infiltration predicts breast cancer survival. The Journal of Clinical Investigation, 123(7), 2873–2892.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Cimino-Mathews, A., Ye, X., Meeker, A., Argani, P., & Emens, L. A. (2013). Metastatic triple-negative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: a pilot study. Human Pathology, 44(10), 2055–2063.Google Scholar
  25. 25.
    Ono, M., Tsuda, H., Shimizu, C., Yamamoto, S., Shibata, T., Yamamoto, H., et al. (2012). Tumor-infiltrating lymphocytes are correlated with response to neoadjuvant chemotherapy in triple-negative breast cancer. Breast Cancer Research and Treatment, 132(3), 793–805.PubMedGoogle Scholar
  26. 26.
    Lee, H. J., Seo, J.-Y., Ahn, J.-H., Ahn, S.-H., & Gong, G. (2013). Tumor-associated lymphocytes predict response to neoadjuvant chemotherapy in breast cancer patients. Journal of Breast Cancer, 16(1), 32–39.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Denkert, C., Loibl, S., Noske, A., Roller, M., Müller, B. M., Komor, M., et al. (2010). Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. Journal of Clinical Oncology, 28(1), 105–113.PubMedGoogle Scholar
  28. 28.
    West, N. R., Milne, K., Truong, P. T., Macpherson, N., Nelson, B. H., & Watson, P. H. (2011). Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Research, 13(6), R126.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Loi, S., Sirtaine, N., Piette, F., Salgado, R., Viale, G., Van Eenoo, F., et al. (2013). Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. Journal of Clinical Oncology, 31(7), 860–867.PubMedGoogle Scholar
  30. 30.
    Andre, F., Dieci, M. V., Dubsky, P., Sotiriou, C., Curigliano, G., Denkert, C., et al. (2013). Molecular pathways: involvement of immune pathways in the therapeutic response and outcome in breast cancer. Clinical Cancer Research, 19(1), 28–33.PubMedGoogle Scholar
  31. 31.
    Song, G., Wang, X., Jia, J., Yuan, Y., Wan, F., Zhou, X., et al. (2013). Elevated level of peripheral CD8(+)CD28(−) T lymphocytes are an independent predictor of progression-free survival in patients with metastatic breast cancer during the course of chemotherapy. Cancer Immunology, Immunotherapy, 62(6), 1123–1130.PubMedGoogle Scholar
  32. 32.
    Loi, S. (2013). Tumor-infiltrating lymphocytes, breast cancer subtypes and therapeutic efficacy. Oncoimmunology, 2(7), e24720.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Chan, M. S. M., Wang, L., Felizola, S. J. A., Ueno, T., Toi, M., Loo, W., et al. (2012). Changes of tumor infiltrating lymphocyte subtypes before and after neoadjuvant endocrine therapy in estrogen receptor-positive breast cancer patients–an immunohistochemical study of Cd8+ and Foxp3+ using double immunostaining with correlation to the path. The International Journal of Biological Markers, 27(4), e295–e304.PubMedGoogle Scholar
  34. 34.
    Zitvogel, L., Apetoh, L., Ghiringhelli, F., & Kroemer, G. (2008). Immunological aspects of cancer chemotherapy. Nature Reviews. Immunology, 8(1), 59–73.PubMedGoogle Scholar
  35. 35.
    Casares, N., Pequignot, M. O., Tesniere, A., Ghiringhelli, F., Roux, S., Chaput, N., et al. (2005). Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. The Journal of Experimental Medicine, 202(12), 1691–1701.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Obeid, M., Tesniere, A., Ghiringhelli, F., Fimia, G. M., Apetoh, L., Perfettini, J. L., et al. (2007). Calreticulin exposure dictates the immunogenicity of cancer cell death. Nature Medicine, 13(1), 54–61.PubMedGoogle Scholar
  37. 37.
    Disis, M. L., Bernhard, H., & Jaffee, E. M. (2009). Use of tumour-responsive T cells as cancer treatment. Lancet, 373(9664), 673–683.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Osmond, D. G. (1994). Production and selection of B lymphocytes in bone marrow: lymphostromal interactions and apoptosis in normal, mutant and transgenic mice. Advances in Experimental Medicine and Biology, 355, 15–20.PubMedGoogle Scholar
  39. 39.
    Stefanovic, S., Schuetz, F., Sohn, C., Beckhove, P., & Domschke, C. (2013). Bone marrow microenvironment in cancer patients: immunological aspects and clinical implications. Cancer Metastasis Reviews, 32(1–2), 163–178.PubMedGoogle Scholar
  40. 40.
    Feuerer, M., Beckhove, P., Garbi, N., Mahnke, Y., Limmer, A., Hommel, M., et al. (2003). Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nature Medicine, 9(9), 1151–1157.PubMedGoogle Scholar
  41. 41.
    Schirrmacher, V., Feuerer, M., Fournier, P., Ahlert, T., Umansky, V., & Beckhove, P. (2003). T-cell priming in bone marrow: the potential for long-lasting protective anti-tumor immunity. Trends in Molecular Medicine, 9(12), 526–534.PubMedGoogle Scholar
  42. 42.
    Mazo, I. B., Honczarenko, M., Leung, H., Cavanagh, L. L., Bonasio, R., Weninger, W., et al. (2005). Bone marrow is a major reservoir and site of recruitment for central memory CD8+ T cells. Immunity, 22(2), 259–270.PubMedGoogle Scholar
  43. 43.
    Feuerer, M., Beckhove, P., Mahnke, Y., Hommel, M., Kyewski, B., Hamann, A., et al. (2004). Bone marrow microenvironment facilitating dendritic cell: CD4 T cell interactions and maintenance of CD4 memory. International Journal of Oncology, 25(4), 867–876.PubMedGoogle Scholar
  44. 44.
    Khazaie, K., Prifti, S., Beckhove, P., Griesbach, A., Russell, S., Collins, M., et al. (1994). Persistence of dormant tumor cells in the bone marrow of tumor cell-vaccinated mice correlates with long-term immunological protection. Proceedings of the National Academy of Sciences of the United States of America, 91(16), 7430–7434.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Schirrmacher, V., Feuerer, M., Beckhove, P., Ahlert, T., & Umansky, V. (2002). T cell memory, anergy and immunotherapy in breast cancer. Journal of Mammary Gland Biology and Neoplasia, 7(2), 201–208.PubMedGoogle Scholar
  46. 46.
    Mahnke, Y. D., Schwendemann, J., Beckhove, P., & Schirrmacher, V. (2005). Maintenance of long-term tumour-specific T-cell memory by residual dormant tumour cells. Immunology, 115(3), 325–336.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Müller, M., Gounari, F., Prifti, S., Hacker, H. J., Schirrmacher, V., & Khazaie, K. (1998). EblacZ tumor dormancy in bone marrow and lymph nodes: active control of proliferating tumor cells by CD8+ immune T cells. Cancer Research, 58(23), 5439–5446.PubMedGoogle Scholar
  48. 48.
    Bai, L., Beckhove, P., Feuerer, M., Umansky, V., Choi, C., Solomayer, F. S. E.-F., et al. (2003). Cognate interactions between memory T cells and tumor antigen-presenting dendritic cells from bone marrow of breast cancer patients: bidirectional cell stimulation, survival and antitumor activity in vivo. International Journal of Cancer, 103(1), 73–83.Google Scholar
  49. 49.
    Goldrath, A. W., & Bevan, M. J. (1999). Selecting and maintaining a diverse T-cell repertoire. Nature, 402(6759), 255–262.PubMedGoogle Scholar
  50. 50.
    Lanzavecchia, A., & Sallusto, F. (2000). From synapses to immunological memory: the role of sustained T cell stimulation. Current Opinion in Immunology, 12(1), 92–98.PubMedGoogle Scholar
  51. 51.
    Zinkernagel, R. M., Bachmann, M. F., Kündig, T. M., Oehen, S., Pirchet, H., & Hengartner, H. (1996). On immunological memory. Annual Review of Immunology, 14, 333–367.PubMedGoogle Scholar
  52. 52.
    Schwendemann, J., Choi, C., Schirrmacher, V., & Beckhove, P. (2005). Dynamic differentiation of activated human peripheral blood CD8+ and CD4+ effector memory T cells. Journal of Immunology, 175(3), 1433–1439.Google Scholar
  53. 53.
    Hamann, D., Baars, P. A., Rep, M. H., Hooibrink, B., Kerkhof-Garde, S. R., Klein, M. R., et al. (1997). Phenotypic and functional separation of memory and effector human CD8+ T cells. The Journal of Experimental Medicine, 186(9), 1407–1418.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Sallusto, F., Lenig, D., Förster, R., Lipp, M., & Lanzavecchia, A. (1999). Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature, 401(6754), 708–712.PubMedGoogle Scholar
  55. 55.
    Veiga-Fernandes, H., Walter, U., Bourgeois, C., McLean, A., & Rocha, B. (2000). Response of naïve and memory CD8+ T cells to antigen stimulation in vivo. Nature Immunology, 1(1), 47–53.PubMedGoogle Scholar
  56. 56.
    Choi, C., Witzens, M., Bucur, M., Feuerer, M., Sommerfeldt, N., Trojan, A., et al. (2005). Enrichment of functional CD8 memory T cells specific for MUC1 in bone marrow of patients with multiple myeloma. Blood, 105(5), 2132–2134.PubMedGoogle Scholar
  57. 57.
    Feuerer, M., Beckhove, P., Bai, L., Solomayer, E. F., Bastert, G., Diel, I. J., et al. (2001). Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow. Nature Medicine, 7(4), 452–458.PubMedGoogle Scholar
  58. 58.
    Müller-Berghaus, J., Ehlert, K., Ugurel, S., Umansky, V., Bucur, M., Schirrmacher, V., et al. (2006). Melanoma-reactive T cells in the bone marrow of melanoma patients: association with disease stage and disease duration. Cancer Research, 66(12), 5997–6001.PubMedGoogle Scholar
  59. 59.
    Sommerfeldt, N., Schütz, F., Sohn, C., Förster, J., Schirrmacher, V., & Beckhove, P. (2006). The shaping of a polyvalent and highly individual T-cell repertoire in the bone marrow of breast cancer patients. Cancer Research, 66(16), 8258–8265.PubMedGoogle Scholar
  60. 60.
    Solomayer, E.-F., Feuerer, M., Bai, L., Umansky, V., Beckhove, P., Meyberg, G. C., et al. (2003). Influence of adjuvant hormone therapy and chemotherapy on the immune system analysed in the bone marrow of patients with breast cancer. Clinical Cancer Research, 9(1), 174–180.PubMedGoogle Scholar
  61. 61.
    Feuerer, M., Rocha, M., Bai, L., Umansky, V., Solomayer, E. F., Bastert, G., et al. (2001). Enrichment of memory T cells and other profound immunological changes in the bone marrow from untreated breast cancer patients. International Journal of Cancer, 92(1), 96–105.Google Scholar
  62. 62.
    Kämmerer, U., Thanner, F., Kapp, M., Dietl, J., & Sütterlin, M. (2003). Expression of tumor markers on breast and ovarian cancer cell lines. Anticancer Research, 23(2A), 1051–1055.PubMedGoogle Scholar
  63. 63.
    Jiang, X. P., Yang, D. C., Elliott, R. L., & Head, J. F. (2000). Vaccination with a mixed vaccine of autogenous and allogeneic breast cancer cells and tumor associated antigens CA15–3, CEA and CA125—results in immune and clinical responses in breast cancer patients. Cancer Biotherapy & Radiopharmaceuticals, 15(5), 495–505.Google Scholar
  64. 64.
    Bai, L., Feuerer, M., Beckhove, P., Umansky, V., & Schirrmacher, V. (2002). Generation of dendritic cells from human bone marrow mononuclear cells: advantages for clinical application in comparison to peripheral blood monocyte derived cells. International Journal of Oncology, 20(2), 247–253.PubMedGoogle Scholar
  65. 65.
    Beckhove, P., Feuerer, M., Dolenc, M., Schuetz, F., Choi, C., Sommerfeldt, N., et al. (2004). Specifically activated memory T cell subsets from cancer patients recognize and reject xenotransplanted autologous tumors. The Journal of Clinical Investigation, 114(1), 67–76.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Schuetz, F., Ehlert, K., Ge, Y., Schneeweiss, A., Rom, J., Inzkirweli, N., et al. (2009). Treatment of advanced metastasized breast cancer with bone marrow-derived tumour-reactive memory T cells: a pilot clinical study. Cancer Immunology, Immunotherapy, 58(6), 887–900.PubMedGoogle Scholar
  67. 67.
    Yee, C., Thompson, J. A., Roche, P., Byrd, D. R., Lee, P. P., Piepkorn, M., et al. (2000). Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of t cell-mediated vitiligo. The Journal of Experimental Medicine, 192(11), 1637–1644.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Dudley, M. E., Wunderlich, J. R., Yang, J. C., Hwu, P., Schwartzentruber, D. J., Topalian, S. L., et al. (2002). A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. Journal of Immunotherapy, 25(3), 243–251.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Domschke, C., Ge, Y., Bernhardt, I., Schott, S., Keim, S., Juenger, S., et al. (2013). Long-term survival after adoptive bone marrow T cell therapy of advanced metastasized breast cancer: follow-up analysis of a clinical pilot trial. Cancer Immunology, Immunotherapy, 62(6), 1053–1060.PubMedGoogle Scholar
  70. 70.
    Chirgwin, J. M., & Guise, T. A. (2000). Molecular mechanisms of tumor–bone interactions in osteolytic metastases. Critical Reviews in Eukaryotic Gene Expression, 10(2), 159–178.PubMedGoogle Scholar
  71. 71.
    Domschke, C., Schuetz, F., Ge, Y., Seibel, T., Falk, C., Brors, B., et al. (2009). Intratumoral cytokines and tumor cell biology determine spontaneous breast cancer-specific immune responses and their correlation to prognosis. Cancer Research, 69(21), 8420–8428.PubMedGoogle Scholar
  72. 72.
    Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A.-K. L., & Flavell, R. A. (2006). Transforming growth factor-beta regulation of immune responses. Annual Review of Immunology, 24, 99–146.PubMedGoogle Scholar
  73. 73.
    Chen, W., Jin, W., Hardegen, N., Lei, K.-J., Li, L., Marinos, N., et al. (2003). Conversion of peripheral CD4+ CD25− naive T cells to CD4+ CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. The Journal of Experimental Medicine, 198(12), 1875–1886.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Saad, E. D., Katz, A., & Buyse, M. (2010). Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical trials. Journal of Clinical Oncology, 28(11), 1958–1962.PubMedGoogle Scholar
  75. 75.
    Schreiber, R. D., Old, L. J., & Smyth, M. J. (2011). Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science, 331(6024), 1565–1570.PubMedGoogle Scholar
  76. 76.
    Vesely, M. D., Kershaw, M. H., Schreiber, R. D., & Smyth, M. J. (2011). Natural innate and adaptive immunity to cancer. Annual Review of Immunology, 29, 235–271.PubMedGoogle Scholar
  77. 77.
    Zhou, G., & Levitsky, H. (2012). Towards curative cancer immunotherapy: overcoming posttherapy tumor escape. Clinical & Developmental Immunology, 2012, 124187.Google Scholar
  78. 78.
    Huehn, J., Siegmund, K., Lehmann, J. C. U., Siewert, C., Haubold, U., Feuerer, M., et al. (2004). Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. The Journal of Experimental Medicine, 199(3), 303–313.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Liu, Z., Kim, J. H., Falo, L. D., & You, Z. (2009). Tumor regulatory T cells potently abrogate antitumor immunity. Journal of Immunology, 182(10), 6160–6167.Google Scholar
  80. 80.
    Bonertz, A., Weitz, J., Pietsch, D.-H. K., Rahbari, N. N., Schlude, C., Ge, Y., et al. (2009). Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. The Journal of Clinical Investigation, 119(11), 3311–3321.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Nummer, D., Suri-Payer, E., Schmitz-Winnenthal, H., Bonertz, A., Galindo, L., Antolovich, D., et al. (2007). Role of tumor endothelium in CD4+ CD25+ regulatory T cell infiltration of human pancreatic carcinoma. Journal of the National Cancer Institute, 99(15), 1188–1199.PubMedGoogle Scholar
  82. 82.
    Sakaguchi, S., Wing, K., Onishi, Y., Prieto-Martin, P., & Yamaguchi, T. (2009). Regulatory T cells: how do they suppress immune responses? International Immunology, 21(10), 1105–1111.PubMedGoogle Scholar
  83. 83.
    Litzinger, M. T., Fernando, R., Curiel, T. J., Grosenbach, D. W., Schlom, J., & Palena, C. (2007). IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. Blood, 110(9), 3192–3201.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Salagianni, M., Lekka, E., Moustaki, A., Iliopoulou, E. G., Baxevanis, C. N., Papamichail, M., et al. (2011). NK cell adoptive transfer combined with Ontak-mediated regulatory T cell elimination induces effective adaptive antitumor immune responses. Journal of Immunology, 186(6), 3327–3335.Google Scholar
  85. 85.
    Zou, W. (2006). Regulatory T cells, tumour immunity and immunotherapy. Nature reviews. Immunology, 6(4), 295–307.PubMedGoogle Scholar
  86. 86.
    Ruter, J., Barnett, B. G., Kryczek, I., Brumlik, M. J., Daniel, B. J., Coukos, G., et al. (2009). Altering regulatory T cell function in cancer immunotherapy: a novel means to boost the efficacy of cancer vaccines. Frontiers in Bioscience, 14, 1761–1770.Google Scholar
  87. 87.
    Beyer, M., & Schultze, J. L. (2006). Regulatory T cells in cancer. Blood, 108(3), 804–811.PubMedGoogle Scholar
  88. 88.
    Petrausch, U., Poehlein, C. H., Jensen, S. M., Twitty, C., Thompson, J. A., Assmann, I., et al. (2009). Cancer immunotherapy: the role regulatory T cells play and what can be done to overcome their inhibitory effects. Current Molecular Medicine, 9(6), 673–682.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Ghiringhelli, F., Menard, C., Puig, P. E., Ladoire, S., Roux, S., Martin, F., et al. (2007). Metronomic cyclophosphamide regimen selectively depletes CD4+ CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunology, Immunotherapy, 56(5), 641–648.PubMedGoogle Scholar
  90. 90.
    Ghiringhelli, F., Larmonier, N., Schmitt, E., Parcellier, A., Cathelin, D., Garrido, C., et al. (2004). CD4+ CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. European Journal of Immunology, 34(2), 336–344.PubMedGoogle Scholar
  91. 91.
    Lutsiak, M. E. C., Semnani, R. T., De Pascalis, R., Kashmiri, S. V. S., Schlom, J., & Sabzevari, H. (2005). Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood, 105(7), 2862–2868.PubMedGoogle Scholar
  92. 92.
    Ge, Y., Domschke, C., Stoiber, N., Schott, S., Heil, J., Rom, J., et al. (2012). Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunological effects and clinical outcome. Cancer Immunology, Immunotherapy, 61(3), 353–362.PubMedGoogle Scholar
  93. 93.
    Dudley, M. E., Wunderlich, J. R., Robbins, P. F., Yang, J. C., Hwu, P., Schwartzentruber, D. J., et al. (2002). Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science, 298(5594), 850–854.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Oelke, M., Maus, M. V., Didiano, D., June, C. H., Mackensen, A., & Schneck, J. P. (2003). Ex vivo induction and expansion of antigen-specific cytotoxic T cells by HLA-Ig-coated artificial antigen-presenting cells. Nature Medicine, 9(5), 619–624.PubMedGoogle Scholar
  95. 95.
    Chmielewski, M., & Abken, H. (2012). CAR T cells transform to trucks: chimeric antigen receptor-redirected T cells engineered to deliver inducible IL-12 modulate the tumour stroma to combat cancer. Cancer Immunology, Immunotherapy, 61(8), 1269–1277.PubMedGoogle Scholar
  96. 96.
    Koehler, P., Schmidt, P., Hombach, A. A., Hallek, M., & Abken, H. (2012). Engineered T cells for the adoptive therapy of B-cell chronic lymphocytic leukaemia. Advances in Hematology, 2012, 595060.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Wu, R., Forget, M.-A., Chacon, J., Bernatchez, C., Haymaker, C., Chen, J. Q., et al. (2012). Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes for metastatic melanoma: current status and future outlook. Cancer Journal, 18(2), 160–175.Google Scholar
  98. 98.
    Ellebaek, E., Iversen, T. Z., Junker, N., Donia, M., Engell-Noerregaard, L., Met, O., et al. (2012). Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose interleukin-2 in metastatic melanoma patients. Journal of Translational Medicine, 10(1), 169.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Radvanyi, L. G., Bernatchez, C., Zhang, M., Fox, P., Miller, P., Chacon, J., et al. (2012). Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clinical Cancer Research, 18(24), 6758–6770.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Besser, M. J., Shapira-Frommer, R., Treves, A. J., Zippel, D., Itzhaki, O., Hershkovitz, L., et al. (2010). Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clinical Cancer Research, 16(9), 2646–2655.PubMedGoogle Scholar
  101. 101.
    West, N. R., Kost, S. E., Martin, S. D., Milne, K., Deleeuw, R. J., Nelson, B. H., et al. (2013). Tumour-infiltrating FOXP3(+) lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer. British Journal of Cancer, 108(1), 155–162.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Oda, N., Shimazu, K., Naoi, Y., Morimoto, K., Shimomura, A., Shimoda, M., et al. (2012). Intratumoral regulatory T cells as an independent predictive factor for pathological complete response to neoadjuvant paclitaxel followed by 5-FU/epirubicin/cyclophosphamide in breast cancer patients. Breast Cancer Research and Treatment, 136(1), 107–116.PubMedGoogle Scholar
  103. 103.
    Shi, H., Liu, L., & Wang, Z. (2012). Improving the efficacy and safety of engineered T cell therapy for cancer. Cancer Letters, 328(2), 191–197.PubMedGoogle Scholar
  104. 104.
    Cordova, A., Toia, F., La Mendola, C., Orlando, V., Meraviglia, S., Rinaldi, G., et al. (2012). Characterization of human γδ T lymphocytes infiltrating primary malignant melanomas. PloS One, 7(11), e49878.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Hadrup, S. R. (2012). The antigen specific composition of melanoma tumor infiltrating lymphocytes? Oncoimmunology, 1(6), 935–936.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Morgan, R. A., Dudley, M. E., Wunderlich, J. R., Hughes, M. S., Yang, J. C., Sherry, R. M., et al. (2006). Cancer regression in patients after transfer of genetically engineered lymphocytes. Science, 314(5796), 126–129.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Johnson, L. A., Morgan, R. A., Dudley, M. E., Cassard, L., Yang, J. C., Hughes, M. S., et al. (2009). Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood, 114(3), 535–546.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Robbins, P. F., Morgan, R. A., Feldman, S. A., Yang, J. C., Sherry, R. M., Dudley, M. E., et al. (2011). Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. Journal of Clinical Oncology, 29(7), 917–924.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Yvon, E., Del Vecchio, M., Savoldo, B., Hoyos, V., Dutour, A., Anichini, A., et al. (2009). Immunotherapy of metastatic melanoma using genetically engineered GD2-specific T cells. Clinical Cancer Research, 15(18), 5852–5860.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Lo, A. S. Y., Ma, Q., Liu, D. L., & Junghans, R. P. (2010). Anti-GD3 chimeric sFv-CD28/T-cell receptor zeta designer T cells for treatment of metastatic melanoma and other neuroectodermal tumors. Clinical Cancer Research, 16(10), 2769–2780.PubMedGoogle Scholar
  111. 111.
    Burns, W. R., Zhao, Y., Frankel, T. L., Hinrichs, C. S., Zheng, Z., Xu, H., et al. (2010). A high molecular weight melanoma-associated antigen-specific chimeric antigen receptor redirects lymphocytes to target human melanomas. Cancer Research, 70(8), 3027–3033.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Stefan Stefanovic
    • 1
  • Florian Schuetz
    • 1
  • Christof Sohn
    • 1
  • Philipp Beckhove
    • 2
  • Christoph Domschke
    • 1
  1. 1.Department of Gynecology and Obstetrics, National Center for Tumor Diseases (NCT)Heidelberg University HospitalHeidelbergGermany
  2. 2.Division of Translational Immunology, Tumor Immunology Program, German Cancer Research Center (DKFZ)National Center for Tumor Diseases (NCT)HeidelbergGermany

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