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Adoptive immunotherapy of metastatic breast cancer: present and future

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Abstract

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.

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References

  1. Demicheli, R. (2001). Tumour dormancy: findings and hypotheses from clinical research on breast cancer. Seminars in Cancer Biology, 11(4), 297–306.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  4. Braun, S., & Naume, B. (2005). Circulating and disseminated tumor cells. Journal of Clinical Oncology, 23(8), 1623–1626.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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. 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.

    PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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. 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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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. 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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  32. Loi, S. (2013). Tumor-infiltrating lymphocytes, breast cancer subtypes and therapeutic efficacy. Oncoimmunology, 2(7), e24720.

    PubMed  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  34. Zitvogel, L., Apetoh, L., Ghiringhelli, F., & Kroemer, G. (2008). Immunological aspects of cancer chemotherapy. Nature Reviews. Immunology, 8(1), 59–73.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  37. Disis, M. L., Bernhard, H., & Jaffee, E. M. (2009). Use of tumour-responsive T cells as cancer treatment. Lancet, 373(9664), 673–683.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  49. Goldrath, A. W., & Bevan, M. J. (1999). Selecting and maintaining a diverse T-cell repertoire. Nature, 402(6759), 255–262.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  77. Zhou, G., & Levitsky, H. (2012). Towards curative cancer immunotherapy: overcoming posttherapy tumor escape. Clinical & Developmental Immunology, 2012, 124187.

    Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    CAS  Google Scholar 

  85. Zou, W. (2006). Regulatory T cells, tumour immunity and immunotherapy. Nature reviews. Immunology, 6(4), 295–307.

    PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  87. Beyer, M., & Schultze, J. L. (2006). Regulatory T cells in cancer. Blood, 108(3), 804–811.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  105. Hadrup, S. R. (2012). The antigen specific composition of melanoma tumor infiltrating lymphocytes? Oncoimmunology, 1(6), 935–936.

    PubMed  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Gynecology and Obstetrics, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany

    Stefan Stefanovic, Florian Schuetz, Christof Sohn & Christoph Domschke

  2. Division of Translational Immunology, Tumor Immunology Program, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), INF 460, 69120, Heidelberg, Germany

    Philipp Beckhove

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  1. Stefan Stefanovic
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  2. Florian Schuetz
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  5. Christoph Domschke
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Correspondence to Christoph Domschke.

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Stefanovic, S., Schuetz, F., Sohn, C. et al. Adoptive immunotherapy of metastatic breast cancer: present and future. Cancer Metastasis Rev 33, 309–320 (2014). https://doi.org/10.1007/s10555-013-9452-6

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