Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Circulating and disseminated tumour cells — mechanisms of immune surveillance and escape

Nature Reviews Clinical Oncology volume 14, pages 155–167 (2017)Cite this article

Subjects

Key Points

  • Cancer cells leaving the immunosuppressive microenvironment of the primary tumour become vulnerable to immune surveillance and require mechanisms of escape from immune-mediated elimination if they are to form metastases

  • Circulating tumour cells (CTCs) and disseminated tumour cells (DTCs) are often detectable in the peripheral blood and bone marrow, respectively, of patients with any of a range of different malignancies

  • CTCs and DTCs exploit a large variety of immune-escape mechanisms, including alterations in the expression of MHC molecules, NK-cell ligands, FAS, FAS ligand (FASL), and immune-checkpoint molecules, such as CD47 and programmed cell death 1 ligand 1 (PD-L1)

  • CTC homing to distant organs can be supported by direct interactions with immune cells during the process of extravasation, and by the effects of inflammatory cytokines in the target organ

  • Future studies must address the important question of how the immune system shapes the molecular composition of CTCs and DTCs during cancer dormancy and metastatic progression

Abstract

Metastatic spread of tumour cells is the main cause of cancer-related deaths. Understanding the mechanisms of tumour-cell dissemination has, therefore, become an important focus for cancer research. In patients with cancer, disseminated cancer cells are often detectable in the peripheral blood as circulating tumour cells (CTCs) and in the bone marrow or lymph nodes as disseminated tumour cells (DTCs). The identification and characterization of CTCs and DTCs has yielded important insights into the mechanisms of metastasis, resulting in a better understanding of the molecular alterations and profiles underlying drug resistance. Given the expanding role of immunotherapies in the treatment of cancer, interactions between tumour cells and immune cells are the subject of intense research. Theoretically, cancer cells that exit the primary tumour site — leaving the protection of the typically immunosuppressive tumour microenvironment — will be more vulnerable to attack by immune effector cells; thus, the survival of tumour cells after dissemination might be the 'Achilles' heel' of metastatic progression. In this Review, we discuss findings relating to the interactions of CTCs and DTCs with the immune system, in the context of cancer immuno-editing, evasion from immune surveillance, and formation of metastases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Systemic immunomodulation and immune escape in the metastatic cascade.
Figure 2: Immune-escape mechanisms of CTCs in the peripheral blood.

Similar content being viewed by others

References

  1. Braun, S. et al. Lack of effect of adjuvant chemotherapy on the elimination of single dormant tumor cells in bone marrow of high-risk breast cancer patients. J. Clin. Oncol. 18, 80–86 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Naume, B. et al. Clinical outcome with correlation to disseminated tumor cell (DTC) status after DTC-guided secondary adjuvant treatment with docetaxel in early breast cancer. J. Clin. Oncol. 32, 3848–3857 (2014).

    Article  PubMed  Google Scholar 

  3. Bidard, F.-C. et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol. 15, 406–414 (2014).

    Article  PubMed  Google Scholar 

  4. Cristofanilli, M. et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N. Engl. J. Med. 351, 781–791 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Braun, S. et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N. Engl. J. Med. 353, 793–802 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Lokody, I. Cancer genetics: the origin and evolution of an ancient cancer. Nat. Rev. Cancer 14, 152 (2014).

    Article  PubMed  CAS  Google Scholar 

  7. Zhang, L. et al. Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin. Cancer Res. 18, 5701–5710 (2012).

    Article  PubMed  Google Scholar 

  8. Jannasch, K. et al. Chemotherapy of WAP-T mouse mammary carcinomas aggravates tumor phenotype and enhances tumor cell dissemination. Int. J. Cancer 137, 25–36 (2015).

    Article  CAS  PubMed  Google Scholar 

  9. Juacaba, S. F., Horak, E., Price, J. E. & Tarin, D. Tumor cell dissemination patterns and metastasis of murine mammary carcinoma. Cancer Res. 49, 570–575 (1989).

    CAS  PubMed  Google Scholar 

  10. Pantel, K. & Alix-Panabières, C. Bone marrow as a reservoir for disseminated tumor cells: a special source for liquid biopsy in cancer patients. Bonekey Rep. 3, 584 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Pantel, K., Brakenhoff, R. H. & Brandt, B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat. Rev. Cancer 8, 329–340 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Braun, S. & Naume, B. Circulating and disseminated tumor cells. J. Clin. Oncol. 23, 1623–1626 (2005).

    Article  PubMed  Google Scholar 

  13. Bidard, F. C. et al. Disseminated tumor cells and the risk of locoregional recurrence in nonmetastatic breast cancer. Ann. Oncol. 20, 1836–1841 (2009).

    Article  PubMed  Google Scholar 

  14. Kim, M. Y. et al. Tumor self-seeding by circulating cancer cells. Cell 139, 1315–1326 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Pagès, F. et al. Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 29, 1093–1102 (2010).

    Article  PubMed  CAS  Google Scholar 

  16. Crespo, J., Sun, H., Welling, T. H., Tian, Z. & Zou, W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr. Opin. Immunol. 25, 214–221 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Joyce, J. A. & Fearon, D. T. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348, 74–80 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Muller, C. et al. Hematogenous dissemination of glioblastoma multiforme. Sci. Transl. Med. 6, 247ra101 (2014).

    Article  PubMed  CAS  Google Scholar 

  19. Macarthur, K. M. et al. Detection of brain tumor cells in the peripheral blood by a telomerase promoter-based assay. Cancer Res. 74, 2152–2159 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sullivan, J. P. et al. Brain tumor cells in circulation are enriched for mesenchymal gene expression. Cancer Discov. 11, 1299–1309 (2014).

    Article  CAS  Google Scholar 

  21. Pietschmann, S. et al. An individual patient data meta-analysis on characteristics, treatments and outcomes of glioblastoma/gliosarcoma patients with metastases outside of the central nervous system. PLoS ONE 10, e0121592 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Burnet, F. M. The concept of immunological surveillance. Prog. Exp. Tumor Res. 13, 1–27 (1970).

    Article  CAS  PubMed  Google Scholar 

  23. Dunn, G. P., Old, L. J. & Schreiber, R. D. The three Es of cancer immunoediting. Annu. Rev. Immunol. 22, 329–360 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Corthay, A. Does the immune system naturally protect against cancer? Front. Immunol. 5, 197 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Khong, H. T. & Restifo, N. P. Natural selection of tumor variants in the generation of 'tumor escape' phenotypes. Nat. Immunol. 3, 999–1005 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Koebel, C. M. et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450, 903–907 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Teng, M. W. L., Swann, J. B., Koebel, C. M., Schreiber, R. D. & Smyth, M. J. Immune-mediated dormancy: an equilibrium with cancer. J. Leukoc. Biol. 84, 988–993 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Dunn, G. P., Koebel, C. M. & Schreiber, R. D. Interferons, immunity and cancer immunoediting. Nat. Rev. Immunol. 6, 836–848 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Dighe, A. S., Richards, E., Old, L. J. & Schreiber, R. D. Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFNγ receptors. Immunity 1, 447–456 (1994).

    Article  CAS  PubMed  Google Scholar 

  33. Ribas, A. Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov. 5, 915–919 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Oleinika, K., Nibbs, R. J., Graham, G. J. & Fraser, A. R. Suppression, subversion and escape: the role of regulatory T cells in cancer progression. Clin. Exp. Immunol. 171, 36–45 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Facciabene, A., Motz, G. T. & Coukos, G. T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res. 72, 2162–2171 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wu, A. A., Drake, V., Huang, H.-S., Chiu, S. & Zheng, L. Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells. Oncoimmunology 4, e1016700 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Waldhauer, I. & Steinle, A. NK cells and cancer immunosurveillance. Oncogene 27, 5932–5943 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Pantel, K. et al. Frequent down-regulation of major histocompatibility class I antigen expression on individual micrometastatic carcinoma cells. Cancer Res. 51, 4712–4715 (1991).

    CAS  PubMed  Google Scholar 

  40. Green, T. L., Cruse, J. M., Lewis, R. E. & Craft, B. S. Circulating tumor cells (CTCs) from metastatic breast cancer patients linked to decreased immune function and response to treatment. Exp. Mol. Pathol. 95, 174–179 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Santos, M. F. et al. Comparative analysis of innate immune system function in metastatic breast, colorectal, and prostate cancer patients with circulating tumor cells. Exp. Mol. Pathol. 96, 367–374 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Jewett, A. & Tseng, H. Tumor induced inactivation of natural killer cell cytotoxic function; implication in growth, expansion and differentiation of cancer stem cells. J. Cancer 2, 443–457 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Paolino, M. et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507, 508–512 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Green, T. L. et al. Toll-like receptor (TLR) expression of immune system cells from metastatic breast cancer patients with circulating tumor cells. Exp. Mol. Pathol. 97, 44–48 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Bellora, F. et al. TLR activation of tumor-associated macrophages from ovarian cancer patients triggers cytolytic activity of NK cells. Eur. J. Immunol. 44, 1814–1822 (2014).

    Article  CAS  PubMed  Google Scholar 

  46. Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Adib-Conquy, M., Scott-Algara, D., Cavaillon, J.-M. & Souza-Fonseca-Guimaraes, F. TLR-mediated activation of NK cells and their role in bacterial/viral immune responses in mammals. Immunol. Cell Biol. 92, 256–262 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Hanna, N. Role of natural killer cells in control of cancer metastasis. Cancer Metastasis Rev. 1, 45–64 (1982).

    Article  CAS  PubMed  Google Scholar 

  49. Brodbeck, T., Nehmann, N., Bethge, A., Wedemann, G. & Schumacher, U. Perforin-dependent direct cytotoxicity in natural killer cells induces considerable knockdown of spontaneous lung metastases and computer modelling-proven tumor cell dormancy in a HT29 human colon cancer xenograft mouse model. Mol. Cancer 13, 244 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Takeda, K. et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat. Med. 7, 94–100 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Mitchell, M. J., Wayne, E., Rana, K., Schaffer, C. B. & King, M. R. TRAIL-coated leukocytes that kill cancer cells in the circulation. Proc. Natl Acad. Sci. USA 111, 930–935 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gül, N. et al. Macrophages eliminate circulating tumor cells after monoclonal antibody therapy. J. Clin. Invest. 124, 812–823 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Gül, N., Babes, L., Kubes, P. & van Egmond, M. Macrophages in the liver prevent metastasis by efficiently eliminating circulating tumor cells after monoclonal antibody immunotherapy. Oncoimmunology 3, e28441 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Bayon, L., Izquierdo, M. & Sirovich, I. Role of Kupffer cells in arresting circulating tumor cells and controlling metastatic growth in the liver. Hepatology 23, 1224–1231 (1996).

    Article  CAS  PubMed  Google Scholar 

  55. Denève, E. et al. Capture of viable circulating tumor cells in the liver of colorectal cancer patients. Clin. Chem. 59, 1384–1392 (2013).

    Article  PubMed  CAS  Google Scholar 

  56. Van den Eynden, G. G. et al. The multifaceted role of the microenvironment in liver metastasis: biology and clinical implications. Cancer Res. 73, 2031–2043 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Galon, J., Costes, A. & Sanchez-Cabo, F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1965 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Galon, J., Angell, H. K., Bedognetti, D. & Marincola, F. M. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 39, 11–26 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Fridman, W. H. et al. Prognostic and predictive impact of intra- and peritumoral immune infiltrates. Cancer Res. 71, 5601–5605 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Shankaran, V., Ikeda, H. & Bruce, A. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. De Giorgi, U. et al. Relationship between lymphocytopenia and circulating tumor cells as prognostic factors for overall survival in metastatic breast cancer. Clin. Breast Cancer 12, 264–269 (2012).

    Article  PubMed  Google Scholar 

  62. Gruber, I. et al. Relationship between circulating tumor cells and peripheral T-cells in patients with primary breast cancer. Anticancer Res. 33, 2233–2238 (2013).

    CAS  PubMed  Google Scholar 

  63. Mego, M. et al. Circulating tumor cells (CTC) are associated with defects in adaptive immunity in patients with inflammatory breast cancer. J. Cancer 7, 1095–1104 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Chang, Y. S. et al. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc. Natl Acad. Sci. USA 97, 14608–14613 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Dougan, M. & Dranoff, G. in Current Protocols in Immunology. Ch. 20, Unit 20.11 (ed. Coico, R.) (Wiley, 2009).

    Google Scholar 

  66. Aptsiauri, N. et al. Role of altered expression of HLA class I molecules in cancer progression. Adv. Exp. Med. Biol. 601, 123–131 (2007).

    Article  PubMed  Google Scholar 

  67. Placke, T. et al. Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Res. 72, 440–448 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Gay, L. & Felding-Habermann, B. Contribution of platelets to tumour metastasis. Nat. Rev. Cancer 11, 123–134 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Labelle, M., Begum, S. & Hynes, R. O. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 20, 576–590 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Palumbo, J. S. et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell – mediated elimination of tumor cells. Blood 105, 178–186 (2014).

    Article  CAS  Google Scholar 

  71. Camerer, E. et al. Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. Blood 104, 397–401 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Leblanc, R. & Peyruchaud, O. Metastasis: new functional implications of platelets and megakaryocytes. Blood 128, 24–31 (2016).

    Article  CAS  PubMed  Google Scholar 

  73. Wu, M.-S., Li, C.-H., Ruppert, J. G. & Chang, C.-C. Cytokeratin 8–MHC class I interactions: a potential novel immune escape phenotype by a lymph node metastatic carcinoma cell line. Biochem. Biophys. Res. Commun. 441, 618–623 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. Moll, R., Franke, W., Schiller, D., Geiger, B. & Krepler, R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 31, 11–24 (1982).

    Article  CAS  PubMed  Google Scholar 

  75. Nausch, N. & Cerwenka, A. NKG2D ligands in tumor immunity. Oncogene 27, 5944–5958 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Wang, B. et al. Metastatic consequences of immune escape from NK cell cytotoxicity by human breast cancer stem cells. Cancer Res. 74, 5746–5757 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. Barsoum, I. B. et al. Hypoxia induces escape from innate immunity in cancer cells via increased expression of ADAM10: role of nitric oxide. Cancer Res. 71, 7433–7441 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Crane, C. A. et al. Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients. Proc. Natl Acad. Sci. USA 5, 12823–12828 (2014).

    Article  CAS  Google Scholar 

  79. Deng, W. et al. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection. Science 348, 136–139 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kochan, G., Escors, D., Breckpot, K. & Guerrero-Setas, D. Role of non-classical MHC class I molecules in cancer immunosuppression. Oncoimmunology 2, e26491 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Lin, A. & Yan, W.-H. HLA-G expression in cancers: roles in immune evasion, metastasis and target for therapy. Mol. Med. 21, 782–791 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. He, X. et al. HLA-G expression in human breast cancer: implications for diagnosis and prognosis, and effect on allocytotoxic lymphocyte response after hormone treatment in vitro. Ann. Surg. Oncol. 17, 1459–1469 (2010).

    Article  PubMed  Google Scholar 

  83. de Kruijf, E. M. et al. HLA-E and HLA-G expression in classical HLA class I-negative tumors is of prognostic value for clinical outcome of early breast cancer patients. J. Immunol. 185, 7452–7459 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Guo, Z.-Y. et al. Predictive value of HLA-G and HLA-E in the prognosis of colorectal cancer patients. Cell. Immunol. 293, 10–16 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Cai, M.-Y. et al. Human leukocyte antigen-G protein expression is an unfavorable prognostic predictor of hepatocellular carcinoma following curative resection. Clin. Cancer Res. 15, 4686–4693 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Wiendl, H. et al. A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape. J. Immunol. 168, 4772–4780 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Loumagne, L. et al. In vivo evidence that secretion of HLA-G by immunogenic tumor cells allows their evasion from immunosurveillance. Int. J. Cancer 135, 2107–2117 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. Agaugué, S., Carosella, E. D. & Rouas-Freiss, N. Role of HLA-G in tumor escape through expansion of myeloid-derived suppressor cells and cytokinic balance in favor of Th2 versus Th1/Th17. Blood 117, 7021–7031 (2011).

    Article  PubMed  CAS  Google Scholar 

  89. Contini, P. et al. Soluble HLA-A,-B,-C and -G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation. Eur. J. Immunol. 33, 125–134 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. König, L. et al. The prognostic impact of soluble and vesicular HLA-G and its relationship to circulating tumor cells in neoadjuvant treated breast cancer patients. Hum. Immunol. 77, 791–799 (2016).

    Article  PubMed  CAS  Google Scholar 

  91. Owen-Schaub, L., Chan, H., Cusack, J. C., Roth, J. & Hill, L. L. Fas and Fas ligand interactions in malignant disease. Int. J. Oncol. 17, 5–12 (2000).

    CAS  PubMed  Google Scholar 

  92. Terheyden, P. et al. Predominant expression of Fas (CD95) ligand in metastatic melanoma revealed by longitudinal analysis. J. Invest. Dermatol. 112, 899–902 (1999).

    Article  CAS  PubMed  Google Scholar 

  93. Nozoe, T., Yasuda, M., Honda, M., Inutsuka, S. & Korenaga, D. Fas ligand expression is correlated with metastasis in colorectal carcinoma. Oncology 65, 83–88 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Gutierrez, L. S., Eliza, M., Niven-Fairchild, T., Naftolin, F. & Mor, G. The Fas/Fas-ligand system: a mechanism for immune evasion in human breast carcinomas. Breast Cancer Res. Treat. 54, 245–253 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Gordon, N. & Kleinerman, E. S. The role of Fas/FasL in the metastatic potential of osteosarcoma and targeting this pathway for the treatment of osteosarcoma lung metastases. Cancer Treat. Res. 152, 497–508 (2009).

    Article  PubMed  Google Scholar 

  96. Owen-Schaub, L. B., van Golen, K. L., Hill, L. L. & Price, J. E. Fas and Fas ligand interactions suppress melanoma lung metastasis. J. Exp. Med. 188, 1717–1723 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Strand, S. et al. Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells — a mechanism of immune evasion? Nat. Med. 2, 1361–1366 (1996).

    Article  CAS  PubMed  Google Scholar 

  98. Gruber, I. V. et al. Down-regulation of CD28, TCR-zeta (ζ) and up-regulation of FAS in peripheral cytotoxic T-cells of primary breast cancer patients. Anticancer Res. 28, 779–784 (2008).

    CAS  PubMed  Google Scholar 

  99. Strauss, L., Bergmann, C. & Whiteside, T. L. Human circulating CD4+CD25highFoxp3+ regulatory T cells kill autologous CD8+ but not CD4+ responder cells by Fas-mediated apoptosis. J. Immunol. 182, 1469–1480 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Ugurel, S., Rappl, G., Tilgen, W. & Reinhold, U. Increased soluble CD95 (sFas/CD95) serum level correlates with poor prognosis in melanoma patients. Clin. Cancer Res. 7, 1282–1286 (2001).

    CAS  PubMed  Google Scholar 

  101. Cheng, J. et al. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science 263, 1759–1762 (1994).

    Article  CAS  PubMed  Google Scholar 

  102. Hallermalm, K., De Geer, A., Kiessling, R., Levitsky, V. & Levitskaya, J. Autocrine secretion of Fas ligand shields tumor cells from Fas-mediated killing by cytotoxic lymphocytes. Cancer Res. 64, 6775–6782 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Kim, R., Emi, M., Tanabe, K. & Arihiro, K. Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res. 66, 5527–5536 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Chao, M. P., Majeti, R. & Weissman, I. L. Programmed cell removal: a new obstacle in the road to developing cancer. Nat. Rev. Cancer 12, 58–67 (2011).

    Article  PubMed  CAS  Google Scholar 

  105. Jaiswal, S. et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271–285 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Steinert, G. et al. Immune escape and survival mechanisms in circulating tumor cells of colorectal cancer. Cancer Res. 74, 1694–1704 (2014).

    Article  CAS  PubMed  Google Scholar 

  107. Chao, M. P. et al. Extranodal dissemination of non-Hodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy. Blood 118, 4890–4901 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Baccelli, I. et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat. Biotechnol. 31, 539–544 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. Baccelli, I. et al. Co-expression of MET and CD47 is a novel prognosticator for survival of luminal-type breast cancer patients. Oncotarget 5, 8147–8160 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Noman, M. Z., Messai, Y., Muret, J., Hasmim, M. & Chouaib, S. Crosstalk between CTC, immune system and hypoxic tumor microenvironment. Cancer Microenviron. 7, 153–160 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kallergi, G. et al. Hypoxia-inducible factor-α and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients. Breast Cancer Res. 11, R84 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Bartkowiak, K., Riethdorf, S. & Pantel, K. The interrelating dynamics of hypoxic tumor microenvironments and cancer cell phenotypes in cancer metastasis. Cancer Microenviron. 5, 59–72 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Bartkowiak, K. et al. Disseminated tumor cells persist in the bone marrow of breast cancer patients through sustained activation of the unfolded protein response. Cancer Res. 75, 5367–5377 (2015).

    Article  CAS  PubMed  Google Scholar 

  114. Barrett, D. M., Singh, N., Porter, D. L., Grupp, S. A. & June, C. H. Chimeric antigen receptor therapy for cancer. Annu. Rev. Med. 65, 333–347 (2014).

    Article  CAS  PubMed  Google Scholar 

  115. Sharma, P. The future of immune checkpoint therapy. Science 348, 56–61 (2014).

    Article  CAS  Google Scholar 

  116. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zou, W. & Chen, L. Inhibitory B7-family molecules in the tumour microenvironment. Nat. Rev. Immunol. 8, 467–477 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. Mego, M. et al. Prognostic value of EMT-circulating tumor cells in metastatic breast cancer patients undergoing high-dose chemotherapy with autologous hematopoietic stem cell transplantation. J. Cancer 3, 369–380 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Joosse, S. A., Gorges, T. M. & Pantel, K. Biology, detection, and clinical implications of circulating tumor cells. EMBO Mol. Med. 7, 1–11 (2014).

    Article  PubMed Central  CAS  Google Scholar 

  120. Alsuliman, A. et al. Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: significance in claudin-low breast cancer cells. Mol. Cancer 14, 149 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Chen, L. et al. Metastasis is regulated via microRNA- 200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat. Commun. 5, 5241 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. Wang, Y. et al. PD-L1 induces epithelial-to-mesenchymal transition via activating SREBP-1c in renal cell carcinoma. Med. Oncol. 32, 212 (2015).

    Article  PubMed  CAS  Google Scholar 

  123. Ock, C.-Y. et al. PD-L1 expression is associated with epithelial–mesenchymal transition in head and neck squamous cell carcinoma. Oncotarget 7, 15901–15914 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Lee, Y. et al. CD44+ cells in head and neck squamous cell carcinoma suppress T-cell-mediated immunity by selective constitutive and inducible expression of PD-L1. Clin. Cancer Res. 22, 3571–3581 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Cohen, E. N. et al. Inflammation mediated metastasis: immune induced epithelial-to-mesenchymal transition in inflammatory breast cancer cells. PLoS ONE 10, e0132710 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Mego, M. et al. CXCR4–SDF-1 interaction potentially mediates trafficking of circulating tumor cells in primary breast cancer. BMC Cancer 16, 127 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Shin, D. S. & Ribas, A. The evolution of checkpoint blockade as a cancer therapy: what's here, what's next? Curr. Opin. Immunol. 33, 23–35 (2015).

    Article  CAS  PubMed  Google Scholar 

  128. Romagné, F. et al. Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells. Blood 114, 2667–2677 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Benson, D. M. et al. A phase I trial of the anti-KIR antibody IPH2101 and lenalidomide in patients with relapsed/refractory multiple myeloma. Clin. Cancer Res. 21, 4055–4061 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Mazel, M. et al. Frequent expression of PD-L1 on circulating breast cancer cells. Mol. Oncol. 9, 1773–1782 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. David, R. PD-L1 expression by circulating breast cancer cells. Lancet Oncol. 16, e321 (2015).

    Article  PubMed  Google Scholar 

  132. Oliveira-Costa, J. P. et al. Gene expression patterns through oral squamous cell carcinoma development: PD-L1 expression in primary tumor and circulating tumor cells. Oncotarget 6, 20902–20920 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Jakóbisiak, M., Lasek, W. & Golb, J. Natural mechanisms protecting against cancer. Immunol. Lett. 90, 103–122 (2003).

    Article  PubMed  CAS  Google Scholar 

  134. Smith, H. A. & Kang, Y. The metastasis-promoting roles of tumor-associated immune cells. J. Mol. Med. 91, 411–429 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Kitamura, T., Qian, B.-Z. & Pollard, J. W. Immune cell promotion of metastasis. Nat. Rev. Immunol. 15, 73–86 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Wolf, A. M. et al. Increase of regulatory T cells in the peripheral blood of cancer patients. Clin. Cancer Res. 9, 606–612 (2003).

    PubMed  Google Scholar 

  137. Jiang, H. et al. Elevated chronic inflammatory factors and myeloid-derived suppressor cells indicate poor prognosis in advanced melanoma patients. Int. J. Cancer 136, 2352–2360 (2014).

    Article  PubMed  CAS  Google Scholar 

  138. Wilke, C. M., Wu, K., Zhao, E., Wang, G. & Zou, W. Prognostic significance of regulatory T cells in tumor. Int. J. Cancer 127, 748–758 (2010).

    CAS  PubMed  Google Scholar 

  139. Cole, S. et al. Elevated circulating myeloid derived suppressor cells (MDSC) are associated with inferior overall survival (OS) and correlate with circulating tumor cells (CTC) in patients with metastatic breast cancer. Cancer Res. 69, 4135–4135 (2009).

    Google Scholar 

  140. Stanzer, S. et al. Resistance to apoptosis and expansion of regulatory T cells in relation to the detection of circulating tumor cells in patients with metastatic epithelial cancer. J. Clin. Immunol. 28, 107–114 (2008).

    Article  PubMed  Google Scholar 

  141. Aggouraki, D. et al. Correlation of circulating tumor cells (CTCs) expressing stemness and EMT phenotypes with immunosuppressive cells in metastatic breast cancer patients. Cancer Res. 74, abstr. 3030 (2014).

    Google Scholar 

  142. Hensler, M. et al. Gene expression profiling of circulating tumor cells and peripheral blood mononuclear cells from breast cancer patients. Oncoimmunology 5, e1102827 (2016).

    Article  PubMed  CAS  Google Scholar 

  143. Zhang, P. et al. PARP-1 controls immunosuppressive function of regulatory T cells by destabilizing Foxp3. PLoS ONE 8, e71590 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Taranova, A. G. et al. Allergic pulmonary inflammation promotes the recruitment of circulating tumor cells to the lung. Cancer Res. 68, 8582–8589 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Tseng, J.-Y. et al. Interleukin-17A modulates circulating tumor cells in tumor draining vein of colorectal cancers and affects metastases. Clin. Cancer Res. 20, 2885–2897 (2014).

    Article  CAS  PubMed  Google Scholar 

  146. Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Hiratsuka, S., Watanabe, A., Aburatani, H. & Maru, Y. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat. Cell Biol. 8, 1369–1375 (2006).

    Article  CAS  PubMed  Google Scholar 

  148. Connelly, L. et al. NF-κB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model. Breast Cancer Res. 13, R83 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Jacobs, P. P. & Sackstein, R. CD44 and HCELL: preventing hematogenous metastasis at step 1. FEBS Lett. 585, 3148–3158 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Gakhar, G. et al. Circulating tumor cells from prostate cancer patients interact with E-selectin under physiologic blood flow. PLoS ONE 8, e85143 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Lee, N., Barthel, S. R. & Schatton, T. Melanoma stem cells and metastasis: mimicking hematopoietic cell trafficking? Lab. Invest. 94, 13–30 (2014).

    Article  CAS  PubMed  Google Scholar 

  152. McDonald, B. et al. Systemic inflammation increases cancer cell adhesion to hepatic sinusoids by neutrophil mediated mechanisms. Int. J. Cancer 125, 1298–1305 (2009).

    Article  CAS  PubMed  Google Scholar 

  153. Kate, M. Ten & Aalbers, A. Polymorphonuclear leukocytes increase the adhesion of circulating tumor cells to microvascular endothelium. Anticancer Res. 27, 17–22 (2007).

    PubMed  Google Scholar 

  154. Spicer, J. D. et al. Neutrophils promote liver metastasis via Mac-1-mediated interactions with circulating tumor cells. Cancer Res. 72, 3919–3927 (2012).

    Article  CAS  PubMed  Google Scholar 

  155. Strell, C., Lang, K., Niggemann, B., Zaenker, K. S. & Entschladen, F. Neutrophil granulocytes promote the migratory activity of MDA-MB-468 human breast carcinoma cells via ICAM-1. Exp. Cell Res. 316, 138–148 (2010).

    Article  CAS  PubMed  Google Scholar 

  156. Huh, S. J., Liang, S., Sharma, A., Dong, C. & Robertson, G. P. Transiently entrapped circulating tumor cells interact with neutrophils to facilitate lung metastasis development. Cancer Res. 70, 6071–6082 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Dong, C. & Slattery, M. Melanoma cell extravasation under flow conditions is modulated by leukocytes and endogenously produced interleukin 8. Mol. Cell. Biochem. 2, 145–159 (2005).

    Google Scholar 

  158. Dimitroff, C. J., Lee, J. Y., Fuhlbrigge, R. C. & Sackstein, R. A distinct glycoform of CD44 is an L-selectin ligand on human hematopoietic cells. Proc. Natl Acad. Sci. USA 97, 13841–13846 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Hanley, W. D. et al. Variant isoforms of CD44 are P- and L-selectin ligands on colon carcinoma cells. FASEB J. 20, 337–339 (2006).

    Article  CAS  PubMed  Google Scholar 

  160. Demers, M. et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc. Natl Acad. Sci. USA 109, 13076–13081 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Cedervall, J. et al. Neutrophil extracellular traps accumulate in peripheral blood vessels and compromise organ function in tumor-bearing animals. Cancer Res. 75, 2653–2662 (2015).

    Article  CAS  PubMed  Google Scholar 

  162. Alfaro, C. et al. Tumor-produced interleukin-8 attracts human myeloid-derived suppressor cells and elicits extrusion of neutrophil extracellular traps (NETs). Clin. Cancer Res. 22, 3924–3936 (2016).

    Article  CAS  PubMed  Google Scholar 

  163. Cools-Lartigue, J. et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J. Clin. Invest. 123, 3446–3458 (2013).

    Article  CAS  PubMed Central  Google Scholar 

  164. Cayrefourcq, L. et al. Establishment and characterization of a cell line from human circulating colon cancer cells. Cancer Res. 75, 982–901 (2015).

    Article  CAS  Google Scholar 

  165. Yu, M. et al. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science 345, 216–220 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Gates, J. D. et al. Monitoring circulating tumor cells in cancer vaccine trials. Hum. Vaccin. 4, 389–392 (2008).

    Article  CAS  PubMed  Google Scholar 

  167. Stojadinovic, A. et al. Quantification and phenotypic characterization of circulating tumor cells for monitoring response to a preventive HER2/neu vaccine-based immunotherapy for breast cancer: a pilot study. Ann. Surg. Oncol. 14, 3359–3368 (2007).

    Article  PubMed  Google Scholar 

  168. Maheswaran, S. et al. Detection of mutations in EGFR in circulating lung-cancer cells. N. Engl. J. Med. 359, 366–377 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Strati, A. et al. Gene expression profile of circulating tumor cells in breast cancer by RT-qPCR. BMC Cancer 11, 422 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Gasch, C. et al. Heterogeneity of epidermal growth factor receptor status and mutations of KRAS/PIK3CA in circulating tumor cells of patients with colorectal cancer. Clin. Chem. 59, 252–260 (2013).

    Article  CAS  PubMed  Google Scholar 

  171. Zaidi, M. R. & Merlino, G. The two faces of interferon-γ in cancer. Clin. Cancer Res. 17, 6118–6124 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We apologize to all authors who have published excellent work in this field that we could not cite in this concise Review. We also thank Prof. Wolfgang Deppert (Institute for Tumour Biology, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany) and Dr Cécile Maire (Department of Neurosurgery, UKE) for critical reading of the manuscript, as well as Prof. Katrin Lamszus and Prof. Manfred Westphal (Department of Neurosurgery, UKE) for their continuous support of our work. The work of the authors has been supported by the European Research Council (ERC Advanced Investigator Grant DISSECT (to K.P.).

Author information

Authors and Affiliations

  1. Department of Tumour Biology, University Medical Centre Hamburg-Eppendorf, Martinistraße 52, Hamburg, 20246, Germany

    Malte Mohme, Sabine Riethdorf & Klaus Pantel

  2. Department of Neurosurgery, University Medical Centre Hamburg-Eppendorf, Martinistraße 52, Hamburg, 20246, Germany

    Malte Mohme

Authors
  1. Malte Mohme
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sabine Riethdorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Klaus Pantel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Each author made substantial contributions to researching the data, discussions of content, writing, and review/editing of the manuscript.

Corresponding author

Correspondence to Klaus Pantel.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mohme, M., Riethdorf, S. & Pantel, K. Circulating and disseminated tumour cells — mechanisms of immune surveillance and escape. Nat Rev Clin Oncol 14, 155–167 (2017). https://doi.org/10.1038/nrclinonc.2016.144

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2016.144

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer