Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
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:

Immune cell promotion of metastasis

Nature Reviews Immunology volume 15, pages 73–86 (2015)Cite this article

Subjects

Key Points

  • Malignant tumour cells avoid immune attack by cytotoxic immune cells in the primary tumour site by modulating tumour-infiltrating leukocytes, such as myeloid cells and regulatory T (TReg) cells, which can enhance the survival of tumour cells and can promote their dissemination to the metastatic site.

  • Some types of primary tumour secrete systemic factors that recruit immature myeloid cells to the future metastatic site. Establishment of this pre-metastatic niche enhances efficacy of tumour metastasis.

  • Egress from the primary site is promoted by tumour-associated macrophages (TAMs) that increase angiogenesis, enhance tumour cell mobility and invasiveness, and promote extracellular matrix remodelling. TAMs therefore accelerate tumour cell intravasation and systemic tumour cell dissemination.

  • The survival of circulating or arrested tumour cells is increased by platelets, TAMs and TReg cells. These immune cells transmit survival signals and protect tumour cells from immune attack, which promotes the establishment of metastatic foci.

  • A distinct subset of TAMs, termed metastasis-associated macrophages, promotes extravasation and metastatic growth of cancer cells at the metastatic site.

  • Targeting pro-metastatic immune cells, especially macrophages, by neutralizing colony-stimulating factor 1 (CSF1) or CC-chemokine ligand 2 (CCL2), will be an attractive therapeutic strategy.

  • Emerging data suggest that a combination of conventional immunotherapy or chemotherapy and macrophage-modulating therapy may be effective to control or eradicate metastatic cancer.

Abstract

Metastatic disease is the major cause of death from cancer, and immunotherapy and chemotherapy have had limited success in reversing its progression. Data from mouse models suggest that the recruitment of immunosuppressive cells to tumours protects metastatic cancer cells from surveillance by killer cells, which nullifies the effects of immunotherapy and thus establishes metastasis. Furthermore, in most cases, tumour-infiltrating immune cells differentiate into cells that promote each step of the metastatic cascade and thus are novel targets for therapy. In this Review, we describe how tumour-infiltrating immune cells contribute to the metastatic cascade and we discuss potential therapeutic strategies to target these cells.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: A long journey to develop metastatic tumours.
Figure 2: Preparation for a metastatic journey.
Figure 3: Promotion of the first step of metastasis.
Figure 4: Helping to overcome the rate-limiting steps of metastasis.

Similar content being viewed by others

References

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

    CAS  Google Scholar 

  2. Dunn, G. P., Old, L. J. & Schreiber, R. D. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137–148 (2004). References 1 and 2 summarize the concept of tumour immune surveillance and immune escape.

    CAS  PubMed  Google Scholar 

  3. Eyles, J. et al. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J. Clin. Invest. 120, 2030–2039 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Paolino, M. et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507, 508–512 (2014). This is an important paper showing the mechanism of tumour cell escape from NK cell attack.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Bidwell, B. N. et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nature Med. 18, 1224–1231 (2012).

    CAS  PubMed  Google Scholar 

  6. Yaguchi, T. et al. The mechanisms of cancer immunoescape and development of overcoming strategies. Int. J. Hematol. 93, 294–300 (2011).

    PubMed  Google Scholar 

  7. McAllister, S. S. & Weinberg, R. A. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nature Cell Biol. 16, 717–727 (2014). This is an outstanding review that summarizes recent findings regarding the environmental changes that are induced by tumour-derived systemic factors.

    CAS  PubMed  Google Scholar 

  8. De Palma, M. & Lewis, C. E. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23, 277–286 (2013).

    CAS  PubMed  Google Scholar 

  9. Jochems, C. & Schlom, J. Tumor-infiltrating immune cells and prognosis: the potential link between conventional cancer therapy and immunity. Exp. Biol. Med. 236, 567–579 (2011).

    CAS  Google Scholar 

  10. Zhang, Q.-W. et al. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS ONE 7, e50946 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Templeton, A. J. et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J. Natl. Cancer Inst. 106, dju124 (2014).

    PubMed  Google Scholar 

  12. Pollard, J. W. Trophic macrophages in development and disease. Nature Rev. Immunol. 9, 259–270 (2009).

    CAS  Google Scholar 

  13. Lee, H.-W., Choi, H.-J., Ha, S.-J., Lee, K.-T. & Kwon, Y.-G. Recruitment of monocytes/macrophages in different tumor microenvironments. Biochim. Biophys. Acta. 1835, 170–179 (2013).

    CAS  PubMed  Google Scholar 

  14. Cook, J. & Hageman, T. Tumor-associated macrophages and cancer. Curr. Opin. Pharmacol. 13, 595–601 (2013).

    CAS  PubMed  Google Scholar 

  15. DeNardo, D. G. et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kuang, D.-M. et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206, 1327–1337 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kryczek, I. et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J. Exp. Med. 203, 871–881 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Med. 10, 942–949 (2004).

    CAS  PubMed  Google Scholar 

  19. Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: ''N1'' versus ''N2'' TAN. Cancer Cell 16, 183–194 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Talmadge, J. E. & Gabrilovich, D. I. History of myeloid-derived suppressor cells. Nature Rev. Cancer 13, 739–752 (2013).

    CAS  Google Scholar 

  22. Bayne, L. J. et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21, 822–835 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Srivastava, M. K. et al. Myeloid suppressor cell depletion augments antitumor activity in lung cancer. PLoS ONE 7, e40677 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Sawant, A. et al. Depletion of plasmacytoid dendritic cells inhibits tumor growth and prevents bone metastasis of breast cancer cells. J. Immunol. 189, 4258–4265 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Yang, P. et al. TGF-β-miR-34a-CCL22 signaling-induced TReg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell 22, 291–303 (2012). This study shows that recruitment of immunosuppressive cells is required for tumour metastasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Tan, W. et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL–RANK signaling. Nature 470, 548–553 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Tan, M. C. B. et al. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J. Immunol. 182, 1746–1755 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Karavitis, J. et al. Regulation of COX2 expression in mouse mammary tumor cells controls bone metastasis and PGE2-induction of regulatory T cell migration. PLoS ONE 7, e46342 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Chopra, M. et al. Tumor necrosis factor receptor 2-dependent homeostasis of regulatory T cells as a player in TNF-induced experimental metastasis. Carcinogen. 34, 1296–1303 (2013).

    CAS  Google Scholar 

  30. Dalotto-Moreno, T. et al. Targeting galectin-1 overcomes breast cancer-associated immunosuppression and prevents metastatic disease. Cancer Res. 73, 1107–1117 (2013).

    CAS  PubMed  Google Scholar 

  31. Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nature Rev. Immunol. 6, 295–307 (2006).

    CAS  Google Scholar 

  32. Olkhanud, P. B. et al. Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells. Cancer Res. 69, 5996–6004 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Smyth, M. J. et al. CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J. Immunol. 176, 1582–1587 (2006).

    CAS  PubMed  Google Scholar 

  34. Novitskiy, S. V. et al. TGF-β receptor II loss promotes mammary carcinoma progression by TH17 dependent mechanisms. Cancer Discov. 1, 430–441 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Chung, A. S. et al. An interleukin-17–mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nature Med. 19, 1114–1123 (2013).

    CAS  PubMed  Google Scholar 

  36. Zou, W. & Restifo, N. R. TH17 cells in tumour immunity and immunotherapy. Nature Rev. Immunol. 10, 248–256 (2010).

    CAS  Google Scholar 

  37. Li, Q. et al. IL-17 promoted metastasis of non-small-cell lung cancer cells. Immunol. Lett. 148, 144–150 (2012).

    CAS  PubMed  Google Scholar 

  38. Olkhanud, P. B. et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4+ T cells to T-regulatory cells. Cancer Res. 71, 3505–3515 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  41. Hiratsuka, S. et al. The S100A8–serum amyloid A3–TLR4 paracrine cascade establishes a pre-metastatic phase. Nature Cell Biol. 10, 1349–1355 (2008).

    CAS  PubMed  Google Scholar 

  42. Deng, J. et al. S1PR1-STAT3 signaling is crucial for myeloid cell colonization at future metastatic sites. Cancer Cell 21, 642–654 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Erler, J. T. et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Peinado, H. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nature Med. 18, 883–891 (2012).

    CAS  PubMed  Google Scholar 

  45. van Deventer, H. W., Palmieri, D. A., Wu, Q. P., McCook, E. C. & Serody, J. S. Circulating fibrocytes prepare the lung for cancer metastasis by recruiting Ly-6C+ monocytes via CCL2. J. Immunol. 190, 4861–4867 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Gil-Bernabé, A. M. et al. Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood 119, 3164–3175 (2012).

    PubMed  Google Scholar 

  47. Hiratsuka, S. et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2, 289–300 (2002). This is the first description of the systemic effects that enhance metastasis through expression of MMP9 by myeloid cells.

    CAS  PubMed  Google Scholar 

  48. Sceneay, J. et al. Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res. 72, 3906–3911 (2012).

    CAS  PubMed  Google Scholar 

  49. Monteiro, A. C. et al. T cells induce pre-metastatic osteolytic disease and help bone metastases establishment in a mouse model of metastatic breast cancer. PLoS ONE 8, e68171 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Qian, B. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011). This is the first paper showing that pro-metastatic macrophages originate from circulating monocytes. These monocytes and/or macrophages promote tumour cell extravasation and growth.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Lin, E. Y. et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 66, 11238–11246 (2006).

    CAS  PubMed  Google Scholar 

  52. Lin, E. Y. et al. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 193, 727–740 (2001). This is the first report showing that macrophages contribute to tumour metastasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Lin, E. Y. & Pollard, J. W. Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res. 67, 5064–5066 (2007).

    CAS  PubMed  Google Scholar 

  54. Zabuawala, T. et al. An Ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis. Cancer Res. 70, 1323–1333 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Yeo, E. J. et al. Myeloid WNT7b mediates the angiogenic switch and metastasis in breast cancer. Cancer Res. 74, 2962–2973 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Mazzieri, R. et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19, 512–526 (2011).

    CAS  PubMed  Google Scholar 

  57. Mierke, C. T. et al. Endothelial cell's biomechanical properties are regulated by invasive cancer cells. Mol. Biosyst. 8, 1639–1649 (2012).

    CAS  PubMed  Google Scholar 

  58. Wyckoff, J. et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 64, 7022–7029 (2004).

    CAS  PubMed  Google Scholar 

  59. Wyckoff, J. et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 67, 2649–2656 (2007). This is the first in vivo study showing that macrophages lead cancer cells to enter the blood vessel.

    CAS  PubMed  Google Scholar 

  60. Zhou, Z. N. et al. Autocrine HBEGF expression promotes breast cancer intravasation, metastasis and macrophage-independent invasion in vivo. Oncogene 33, 3784–3793 (2014).

    CAS  PubMed  Google Scholar 

  61. Ishihara, D. et al. Wiskott–Aldrich syndrome protein regulates leukocyte-dependent breast cancer metastasis. Cell Rep. 4, 429–436 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Wang, S. et al. Disruption of the SRC-1 gene in mice suppresses breast cancer metastasis without affecting primary tumor formation. Proc. Natl Acad. Sci. USA 106, 151–156 (2009).

    CAS  PubMed  Google Scholar 

  63. Hernandez, L. et al. The EGF/CSF-1 paracrine invasion loop can be triggered by heregulin β1 and CXCL12. Cancer Res. 69, 3221–3227 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Chen, J. et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell 19, 814–816 (2011).

    CAS  Google Scholar 

  65. Sangaletti, S. et al. Macrophage-derived SPARC bridges tumor cell-extracellular matrix interactions toward metastasis. Cancer Res. 68, 9050–9059 (2008).

    CAS  PubMed  Google Scholar 

  66. Gocheva, V. et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev. 24, 241–255 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. DeNardo, D. G. et al. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16, 91–102 (2009). This is the first study that provides evidence that acquired immune cells can regulate the pro-metastatic function of macrophages.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Casazza, A. et al. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24, 695–709 (2013).

    CAS  PubMed  Google Scholar 

  69. Na, Y.-R., Yoon, Y.-N., Son, D.-I. & Seok, S.-H. Cyclooxygenase-2 inhibition blocks M2 macrophage differentiation and suppresses metastasis in murine breast cancer model. PLoS ONE 8, e63451 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Chittezhath, M. et al. Molecular profiling reveals a tumor-promoting phenotype of monocytes and macrophages in human cancer progression. Immunity 41, 815–829 (2014).

    CAS  PubMed  Google Scholar 

  71. Su, S. et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell 25, 605–620 (2014).

    PubMed  Google Scholar 

  72. Rolny, C. et al. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19, 31–44 (2011).

    CAS  PubMed  Google Scholar 

  73. Coussens, L. M., Zitvogel, L. & Palucka, A. K. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 339, 286–291 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).

    CAS  PubMed  Google Scholar 

  75. Rohan, T. E. et al. Tumor microenvironment of metastasis and risk of distant metastasis of breast cancer. J. Natl. Cancer Inst. 106, dju136 (2014).

    PubMed  PubMed Central  Google Scholar 

  76. Philippar, U. et al. A Mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis. Dev. Cell 15, 813–828 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Pignatelli, J. et al. Invasive breast carcinoma cells from patients exhibit MenaINV- and macrophage-dependent transendothelial migration. Sci. Signal. 25, ra112 (2014).

    Google Scholar 

  78. Bekes, E. M. et al. Tumor-recruited neutrophils and neutrophil TIMP-free MMP-9 regulate coordinately the levels of tumor angiogenesis and efficiency of malignant cell intravasation. Am. J. Pathol. 179, 1455–1470 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhou, S.-L. et al. CXCL5 contributes to tumor metastasis and recurrence of intrahepatic cholangiocarcinoma by recruiting infiltrative intratumoral neutrophils. Carcinogen. 35, 597–605 (2014).

    CAS  Google Scholar 

  80. Bald, T. et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507, 109–113 (2014).

    CAS  PubMed  Google Scholar 

  81. Granot, Z. et al. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20, 300–314 (2011).

    Article  CAS  Google Scholar 

  82. Yang, L. et al. Abrogation of TGFβ signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13, 23–35 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Simpson, K. D., Templeton, D. J. & Cross, J. V. Macrophage migration inhibitory factor promotes tumor growth and metastasis by inducing myeloid-derived suppressor cells in the tumor microenvironment. J. Immunol. 189, 5533–5540 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Toh, B. et al. Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLoS Biol. 9, e1001162 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Corzo, C. A. et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med. 207, 2439–2453 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Swierczak, A. et al. The promotion of breast cancer metastasis caused by inhibition of CSF-1R/CSF-1 signaling is blocked by targeting the G-CSF receptor. Cancer Immunol. Res. 2, 765–776 (2014).

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  88. Palumbo, J. S. et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell–mediated elimination of tumor cells. Blood 105, 178–185 (2005).

    CAS  PubMed  Google Scholar 

  89. Palumbo, J. S. et al. Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and -independent mechanisms. Blood 110, 133–141 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Ferjancic, Š. et al. VCAM-1 and VAP-1 recruit myeloid cells that promote pulmonary metastasis in mice. Blood 121, 3289–3297 (2013).

    CAS  PubMed  Google Scholar 

  91. Chen, Q., Zhang, X. H.-F. & Massagué, J. Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 20, 538–549 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Hoos, A., Protsyuk, D. & Borsig, L. Metastatic growth progression caused by PSGL-1-mediated recruitment of monocytes to metastatic sites. Cancer Res. 74, 695–704 (2014).

    CAS  PubMed  Google Scholar 

  93. Viguier, M. et al. Foxp3 expressing CD4+CD25high regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J. Immunol. 173, 1444–1453 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  95. Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nature Rev. Cancer 9, 239–252 (2009).

    CAS  Google Scholar 

  96. Hussell, T. & Bell, T. J. Alveolar macrophages: plasticity in a tissue-specific context. Nature Rev. Immunol. 14, 81–93 (2014).

    CAS  Google Scholar 

  97. Qian, B. et al. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS ONE 4, e6562 (2009). This is the first study showing that a distinct population of macrophages promotes metastasis by enhancing tumour cell extravasation and survival.

    PubMed  PubMed Central  Google Scholar 

  98. Qian, B.-Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhao, L. et al. Recruitment of a myeloid cell subset (CD11b/Gr1mid) via CCL2/CCR2 promotes the development of colorectal cancer liver metastasis. Hepatology 57, 829–839 (2013).

    CAS  PubMed  Google Scholar 

  100. Sanford, D. E. et al. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin. Cancer Res. 19, 3404–3415 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  Google Scholar 

  104. Schumacher, D., Strilic, B., Sirvaraj, K. K., Wettschureck, N. & Offermanns, S. Platelet-derived nucleotides promote tumor-cell transendothelial migration and metastasis via P2Y2 receptor. Cancer Cell 24, 130–137 (2013).

    CAS  PubMed  Google Scholar 

  105. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Ali, K. et al. Inactivation of PI3K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature 510, 407–411 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Furman, R. R. et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 370, 997–1007 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Broz, M. L. et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26, 638–652 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Escobar, G. et al. Genetic engineering of hematopoiesis for targeted IFN-α delivery inhibits breast cancer progression. Sci. Transl Med. 6, 217ra3 (2014).

    PubMed  Google Scholar 

  110. Mantovani, A., Vecchi, A. & Allavena, P. Pharmacological modulation of monocytes and macrophages. Curr. Opin. Pharmacol. 17, 38–44 (2014). This is an outstanding review that summarizes possible therapeutic strategies that target tumour-promoting monocytes and macrophages.

    CAS  PubMed  Google Scholar 

  111. Ries, C. H. et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25, 846–859 (2014).

    CAS  PubMed  Google Scholar 

  112. Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nature Med. 19, 1264–1272 (2013). References 111 and 112 give a rationale to target macrophages for therapies against malignant tumours.

    CAS  PubMed  Google Scholar 

  113. Pienta, K. J. et al. Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer. Invest. New Drugs 31, 760–768 (2013).

    CAS  PubMed  Google Scholar 

  114. D'Incalci, M., Badri, N., Galmarini, C. M. & Allavena, P. Trabectedin, a drug acting on both cancer cells and the tumour microenvironment. Br. J. Cancer 111, 646–650 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Germano, G. et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 23, 249–262 (2013).

    CAS  PubMed  Google Scholar 

  116. Bonapace, L. et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature 515, 130–133 (2014).

    CAS  PubMed  Google Scholar 

  117. Ruffell, B. et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26, 623–637 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Marusyk, A. et al. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature 514, 54–58 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013).

    CAS  PubMed  Google Scholar 

  120. Gabrilovich, D. I. et al. The terminology issue for myeoid-derived suppressor cells. Cancer Res. 67, 425 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Youn, J. I. et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nature Immunol. 14, 211–220 (2013).

    CAS  Google Scholar 

  122. Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nature Rev. Immunol. 12, 253–268 (2012).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  124. Callahan, M. K. & Wolchok, J. D. At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. J. Leukoc. Biol. 94, 41–53 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors apologize to all others whose work they could not cite because of space restrictions. The authors' work presented in this Review article has been supported by US National Institutes of Health grants RO1 CA172451 and PO1CA100324 and by the Wellcome Trust, UK (SIA 101067/Z/13/Z).

Author information

Authors and Affiliations

  1. Medical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK

    Takanori Kitamura, Bin-Zhi Qian & Jeffrey W. Pollard

  2. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10543, New York, USA

    Jeffrey W. Pollard

Authors
  1. Takanori Kitamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bin-Zhi Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeffrey W. Pollard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey W. Pollard.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

FURTHER INFORMATION

ClinicalTrials.gov

PowerPoint slides

Glossary

Metastasis

The spread of malignant tumour cells from the primary tumour site to distant organs (through the lymphatic system or the blood), in which they grow expansively to develop deadly secondary tumours. Individual tumours express different tissue tropisms for metastasis that may partly be due to the systemic education of different tissues to form pre-metastatic niches.

Tumour microenvironment

The tumour-surrounding environment consists of stromal cells such as endothelial cells, immune cells and fibroblasts, as well as the extracellular matrix. It also contains chemokines, cytokines and growth factors derived from tumour cells and tumour-educated stromal cells.

Regulatory T cells

(TReg cells). A distinct population of immunosuppressive CD4+ T cells that are characterized as CD25+FOXP3+.

T helper 17 cells

(TH17 cells). A subset of CD4+ T helper cells that produce interleukin-17. TH17 cells have crucial roles in adaptive immune responses to pathogens.

Regulatory B cells

(BReg cells). A subpopulation of B cells that have immunosuppressive functions and that may protect the host from autoimmune diseases. In mouse mammary tumours, CD19+B220+CD25+ cells are isolated as immunoregulatory cells and termed tumour-evoked BReg cells.

Tumour-associated macrophages

(TAMs). A distinct population of macrophages in the tumour microenvironment that promotes tumour development and progression. TAMs can be identified by the following marker profile (a marker that is unique to mouse or human is indicated by (m) or (h), respectively): CD11b+, CD14+, CD23+ (h), CD34−, CD45+, CD68+, CD117−, CD133−, CD146−, CD163+ (h), CD204+, CD206+, CCR2+, CSF1R+, CXCR4+ (h), F4/80+ (m), GR1− (m), MHC class II+, VEGFR1+ and VEGFR2−. TAM is a generic term that encompasses several identifiable subpopulations with different functions, including TIE2-expressing pro-angiogenic macrophages in the primary tumour. Thus, each population will have a set of canonical macrophage markers, such as CSF1R+GR1−, but will differentially express other markers, such as VEGFR1.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of myeloid cells, the numbers of which are increased in most patients with cancer and in animal models of cancer. These cells are subdivided into monocytic and granulocytic MDSCs.

Plasmacytoid dendritic cells

(pDCs). A small population of DCs that link innate and adaptive immune responses. Although pDCs have pro-inflammatory properties, such as cytokine secretion, they also have immunosuppressive effects. In mice, pDCs are characterized by expression of B220, CD11c, Siglec-H, PDCA1 (also known as CD317) and GR1, and by the absence of CD11b.

Osteoclastogenesis

A process whereby haematopoietic stem cells differentiate into multinucleated osteoclasts with bone-resorbing activity.

Metastasis-associated macrophages

(MAMs). A distinct subset of tumour-associated macrophages that are recruited to the metastatic sites and promote tumour cell dissemination and outgrowth. MAMs originate from inflammatory monocytes and are characterized by the following marker profile in mice: CD11b+, CD31−, CD45+, CCR2+, CXCR4−, F4/80+, LY6C−, LY6G−, TIE2−, VEGFR1+ and VEGFR2−.

Inflammatory monocytes

A subset of monocytes that is recruited to inflammatory sites. They are characterized as CD11b+LY6C+ in mice and CD14hiCD16− in humans. Inflammatory monocytes also express high level of CCR2 and CSF1R but not the neutrophil marker LY6G. In mouse tumour models, inflammatory monocytes are recruited to the primary or metastatic sites by CCL2 and differentiate into tumour-associated macrophages or metastasis-associated macrophages, respectively.

Neutrophil extracellular trap

(NET). An extracellular fibre structure that consists of extruded DNA and antimicrobial proteins released from neutrophils in response to inflammatory stimuli. A major function of NETs is to trap and kill pathogens.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kitamura, T., Qian, BZ. & Pollard, J. Immune cell promotion of metastasis. Nat Rev Immunol 15, 73–86 (2015). https://doi.org/10.1038/nri3789

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3789

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