Skip to main content

Advertisement

SpringerLink
Log in

Tumor-associated macrophages: a short compendium

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Macrophages play an important role in tissue development and homeostasis. They serve as a nexus between adaptive and innate immunity, and employ considerable plasticity. In cancer, they play a pivotal role in chronic inflammation and tumor growth either by directly stimulating the proliferation of cancer cells or by producing angiogenic and lymphangiogenic factors. Although numerous immune cells play an important role in the tumor microenvironment, tumor-associated macrophages (TAMs) are by far the most extensively studied. A better understanding of the role of TAMs in mediating chemo- and radiotherapy resistance and suppressing immunosurveillance has led to numerous strategies targeting TAMs as an anticancer therapy either by targeting them directly or by polarizing TAMs toward a tumoricidal phenotype.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969. https://doi.org/10.1038/nri2448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tang D, Kang R, Coyne CB et al (2012) PAMPs and DAMPs: signal 0 s that spur autophagy and immunity. Immunol Rev 249:158–175. https://doi.org/10.1111/j.1600-065X.2012.01146.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mass E, Ballesteros I, Farlik M et al (2016) Specification of tissue-resident macrophages during organogenesis. Science 353:aaf4238. https://doi.org/10.1126/science.aaf4238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. O’Neill LAJ, Golenbock D, Bowie AG (2013) The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol 13:453–460. https://doi.org/10.1038/nri3446

    Article  CAS  PubMed  Google Scholar 

  5. Ginhoux F, Jung S (2014) Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 14:392–404. https://doi.org/10.1038/nri3671

    Article  CAS  PubMed  Google Scholar 

  6. Cignarella A, Tedesco S, Cappellari R, Fadini GP (2018) The continuum of monocyte phenotypes: experimental evidence and prognostic utility in assessing cardiovascular risk. J Leukoc Biol. https://doi.org/10.1002/jlb.5ru1217-477rr

    Article  PubMed  Google Scholar 

  7. Hamm A, Prenen H, Van Delm W et al (2016) Tumour-educated circulating monocytes are powerful candidate biomarkers for diagnosis and disease follow-up of colorectal cancer. Gut 65:990–1000. https://doi.org/10.1136/gutjnl-2014-308988

    Article  CAS  PubMed  Google Scholar 

  8. Feng A-L, Zhu J-K, Sun J-T et al (2011) CD16+ monocytes in breast cancer patients: expanded by monocyte chemoattractant protein-1 and may be useful for early diagnosis. Clin Exp Immunol 164:57–65. https://doi.org/10.1111/j.1365-2249.2011.04321.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Takeda Y, Costa S, Delamarre E et al (2011) Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis. Nature 479:122–126. https://doi.org/10.1038/nature10507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Madsen DH, Leonard D, Masedunskas A et al (2013) M2-like macrophages are responsible for collagen degradation through a mannose receptor-mediated pathway. J Cell Biol 202:951–966. https://doi.org/10.1083/jcb.201301081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mantovani A, Sozzani S, Locati M et al (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–555

    Article  CAS  PubMed  Google Scholar 

  12. Duluc D, Corvaisier M, Blanchard S et al (2009) Interferon-γ reverses the immunosuppressive and protumoral properties and prevents the generation of human tumor-associated macrophages. Int J Cancer 125:367–373. https://doi.org/10.1002/ijc.24401

    Article  CAS  PubMed  Google Scholar 

  13. Junttila MR, de Sauvage FJ (2013) Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 501:346–354. https://doi.org/10.1038/nature12626

    Article  CAS  PubMed  Google Scholar 

  14. Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795. https://doi.org/10.1172/JCI59643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Biswas SK, Sica A, Lewis CE (2008) Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. J Immunol 180:2011–2017

    Article  CAS  PubMed  Google Scholar 

  16. Zarif JC, Taichman RS, Pienta KJ (2014) TAM macrophages promote growth and metastasis within the cancer ecosystem. Oncoimmunology 3:e941734. https://doi.org/10.4161/21624011.2014.941734

    Article  PubMed  PubMed Central  Google Scholar 

  17. Qian B-Z, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51. https://doi.org/10.1016/j.cell.2010.03.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Elinav E, Nowarski R, Thaiss CA et al (2013) Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 13:759–771. https://doi.org/10.1038/nrc3611

    Article  CAS  PubMed  Google Scholar 

  19. Franklin RA, Liao W, Sarkar A et al (2014) The cellular and molecular origin of tumor-associated macrophages. Science (80-) 344:921–925. https://doi.org/10.1126/science.1252510

    Article  CAS  Google Scholar 

  20. Henze A-T, Mazzone M (2016) The impact of hypoxia on tumor-associated macrophages. J Clin Invest 126:3672–3679. https://doi.org/10.1172/JCI84427

    Article  PubMed  PubMed Central  Google Scholar 

  21. Xiao M, Zhang J, Chen W, Chen W (2018) M1-like tumor-associated macrophages activated by exosome-transferred THBS1 promote malignant migration in oral squamous cell carcinoma. J Exp Clin Cancer Res 37:143. https://doi.org/10.1186/s13046-018-0815-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen X, Ying X, Wang X et al (2017) Exosomes derived from hypoxic epithelial ovarian cancer deliver microRNA-940 to induce macrophage M2 polarization. Oncol Rep 38:522–528. https://doi.org/10.3892/or.2017.5697

    Article  CAS  PubMed  Google Scholar 

  23. Hsieh C-H, Tai S-K, Yang M-H (2018) Snail-overexpressing cancer cells promote M2-like polarization of tumor-associated macrophages by delivering MiR-21-abundant exosomes. Neoplasia 20:775–788. https://doi.org/10.1016/j.neo.2018.06.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mittal D, Gubin MM, Schreiber RD, Smyth MJ (2014) New insights into cancer immunoediting and its three component phases—elimination, equilibrium and escape. Curr Opin Immunol 27:16–25. https://doi.org/10.1016/j.coi.2014.01.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Qian B-Z, Pollard JW (2012) New tricks for metastasis-associated macrophages. Breast Cancer Res 14:316. https://doi.org/10.1186/bcr3143

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ruffell B, Coussens LM (2015) Macrophages and therapeutic resistance in cancer. Cancer Cell 27:462–472. https://doi.org/10.1016/j.ccell.2015.02.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444. https://doi.org/10.1038/nature07205

    Article  CAS  PubMed  Google Scholar 

  28. Mantovani A, Allavena P (2015) The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med 212:435–445. https://doi.org/10.1084/jem.20150295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Koong AC, Chen EY, Mivechi NF et al (1994) Hypoxic activation of nuclear factor-kappa B is mediated by a Ras and Raf signaling pathway and does not involve MAP kinase (ERK1 or ERK2). Cancer Res 54:5273–5279

    CAS  PubMed  Google Scholar 

  30. Minet E, Arnould T, Michel G et al (2000) ERK activation upon hypoxia: involvement in HIF-1 activation. FEBS Lett 468:53–58

    Article  CAS  PubMed  Google Scholar 

  31. Keith B, Johnson RS, Simon MC (2011) HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12:9–22. https://doi.org/10.1038/nrc3183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410. https://doi.org/10.1038/nrc1093

    Article  CAS  PubMed  Google Scholar 

  33. Leite de Oliveira R, Hamm A, Mazzone M (2011) Growing tumor vessels: more than one way to skin a cat—implications for angiogenesis targeted cancer therapies. Mol Aspects Med 32:71–87. https://doi.org/10.1016/j.mam.2011.04.001

    Article  PubMed  Google Scholar 

  34. Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146:873–887. https://doi.org/10.1016/j.cell.2011.08.039

    Article  CAS  PubMed  Google Scholar 

  35. Varricchi G, Loffredo S, Galdiero MR et al (2018) Innate effector cells in angiogenesis and lymphangiogenesis. Curr Opin Immunol 53:152–160. https://doi.org/10.1016/j.coi.2018.05.002

    Article  CAS  PubMed  Google Scholar 

  36. Sherwood LM, Parris EE, Folkman J (1971) Tumor Angiogenesis: therapeutic Implications. N Engl J Med 285:1182–1186. https://doi.org/10.1056/NEJM197111182852108

    Article  Google Scholar 

  37. De Palma M, Biziato D, Petrova TV (2017) Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer 17:457–474. https://doi.org/10.1038/nrc.2017.51

    Article  CAS  PubMed  Google Scholar 

  38. Eubank TD, Galloway M, Montague CM et al (2003) M-CSF induces vascular endothelial growth factor production and angiogenic activity from human monocytes. J Immunol 171:2637–2643

    Article  CAS  PubMed  Google Scholar 

  39. Hill LM, Gavala ML, Lenertz LY, Bertics PJ (2010) Extracellular ATP may contribute to tissue repair by rapidly stimulating purinergic receptor X7-dependent vascular endothelial growth factor release from primary human monocytes. J Immunol 185:3028–3034. https://doi.org/10.4049/jimmunol.1001298

    Article  CAS  PubMed  Google Scholar 

  40. Poulin S, Thompson C, Thivierge M et al (2011) Cysteinyl-leukotrienes induce vascular endothelial growth factor production in human monocytes and bronchial smooth muscle cells. Clin Exp Allergy 41:204–217. https://doi.org/10.1111/j.1365-2222.2010.03653.x

    Article  CAS  PubMed  Google Scholar 

  41. Czepluch FS, Olieslagers S, van Hulten R et al (2011) VEGF-A-induced chemotaxis of CD16+ monocytes is decreased secondary to lower VEGFR-1 expression. Atherosclerosis 215:331–338. https://doi.org/10.1016/j.atherosclerosis.2011.01.004

    Article  CAS  PubMed  Google Scholar 

  42. De Palma M, Venneri MA, Galli R et al (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8:211–226. https://doi.org/10.1016/j.ccr.2005.08.002

    Article  CAS  PubMed  Google Scholar 

  43. Venneri MA, Palma MD, Ponzoni M et al (2007) Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer. Blood 109:5276–5285. https://doi.org/10.1182/blood-2006-10-053504

    Article  CAS  PubMed  Google Scholar 

  44. Matsubara T, Kanto T, Kuroda S et al (2013) TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlates with angiogenesis. Hepatology 57:1416–1425. https://doi.org/10.1002/hep.25965

    Article  CAS  PubMed  Google Scholar 

  45. Turrini R, Pabois A, Xenarios I et al (2017) TIE-2 expressing monocytes in human cancers. Oncoimmunology 6:e1303585. https://doi.org/10.1080/2162402X.2017.1303585

    Article  PubMed  PubMed Central  Google Scholar 

  46. Coffelt SB, Chen Y-Y, Muthana M et al (2011) Angiopoietin 2 stimulates TIE2-expressing monocytes to suppress T cell activation and to promote regulatory T cell expansion. J Immunol 186:4183–4190. https://doi.org/10.4049/jimmunol.1002802

    Article  CAS  PubMed  Google Scholar 

  47. Mazzieri R, Pucci F, Moi D et al (2011) 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. https://doi.org/10.1016/j.ccr.2011.02.005

    Article  CAS  PubMed  Google Scholar 

  48. Lin EY, Li J-F, Gnatovskiy L et al (2006) Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66:11238–11246. https://doi.org/10.1158/0008-5472.CAN-06-1278

    Article  CAS  PubMed  Google Scholar 

  49. Stockmann C, Doedens A, Weidemann A et al (2008) Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456:814–818. https://doi.org/10.1038/nature07445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Priceman SJ, Sung JL, Shaposhnik Z et al (2010) Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy. Blood 115:1461–1471. https://doi.org/10.1182/blood-2009-08-237412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141:52–67. https://doi.org/10.1016/j.cell.2010.03.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fischer C, Jonckx B, Mazzone M et al (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131:463–475. https://doi.org/10.1016/j.cell.2007.08.038

    Article  CAS  PubMed  Google Scholar 

  53. Rolny C, Mazzone M, Tugues S et al (2011) HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19:31–44. https://doi.org/10.1016/j.ccr.2010.11.009

    Article  CAS  PubMed  Google Scholar 

  54. Nozawa H, Chiu C, Hanahan D (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci USA 103:12493–12498. https://doi.org/10.1073/pnas.0601807103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mantovani A (2010) Molecular pathways linking inflammation and cancer. Curr Mol Med 10:369–373

    Article  CAS  PubMed  Google Scholar 

  56. DeNardo DG, Barreto JB, Andreu P et al (2009) CD4+ T Cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16:91–102. https://doi.org/10.1016/j.ccr.2009.06.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Facciabene A, Peng X, Hagemann IS et al (2011) Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 475:226–230. https://doi.org/10.1038/nature10169

    Article  CAS  PubMed  Google Scholar 

  58. Tammela T, Alitalo K (2010) Lymphangiogenesis: molecular mechanisms and future promise. Cell 140:460–476. https://doi.org/10.1016/j.cell.2010.01.045

    Article  CAS  PubMed  Google Scholar 

  59. Wang Y, Oliver G (2010) Current views on the function of the lymphatic vasculature in health and disease. Genes Dev 24:2115–2126. https://doi.org/10.1101/gad.1955910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Joukov V, Pajusola K, Kaipainen A et al (1996) A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 15:290–298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Achen MG, Jeltsch M, Kukk E et al (1998) Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci U S A 95:548–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Alitalo A, Detmar M (2012) Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene 31:4499–4508. https://doi.org/10.1038/onc.2011.602

    Article  CAS  PubMed  Google Scholar 

  63. Hong Y-K (2004) VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the 1 1 and 2 1 integrins. FASEB J 18:1111–1113. https://doi.org/10.1096/fj.03-1179fje

    Article  CAS  PubMed  Google Scholar 

  64. Yuan L, Moyon D, Pardanaud L et al (2002) Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 129:4797–4806

    CAS  PubMed  Google Scholar 

  65. Christiansen A, Detmar M (2011) Lymphangiogenesis and cancer. Genes Cancer 2:1146–1158. https://doi.org/10.1177/1947601911423028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tammela T, Petrova TV, Alitalo K (2005) Molecular lymphangiogenesis: new players. Trends Cell Biol 15:434–441. https://doi.org/10.1016/j.tcb.2005.06.004

    Article  CAS  PubMed  Google Scholar 

  67. Watari K, Shibata T, Kawahara A et al (2014) Tumor-derived interleukin-1 promotes lymphangiogenesis and lymph node metastasis through M2-type macrophages. PLoS One 9:e99568. https://doi.org/10.1371/journal.pone.0099568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Casazza A, Laoui D, Wenes M et al (2013) Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24:695–709. https://doi.org/10.1016/j.ccr.2013.11.007

    Article  CAS  PubMed  Google Scholar 

  69. Cursiefen C, Chen L, Borges LP et al (2004) VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 113:1040–1050. https://doi.org/10.1172/JCI20465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Shree T, Olson OC, Elie BT et al (2011) Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev 25:2465–2479. https://doi.org/10.1101/gad.180331.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Alishekevitz D, Gingis-Velitski S, Kaidar-Person O et al (2016) Macrophage-induced lymphangiogenesis and metastasis following paclitaxel chemotherapy is regulated by VEGFR3. Cell Rep 17:1344–1356. https://doi.org/10.1016/j.celrep.2016.09.083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Thomas L (1982) On immunosurveillance in human cancer. Yale J Biol Med 55:329–333

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Prehn RT, Main JM (1957) Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst 18:769–778

    CAS  PubMed  Google Scholar 

  74. Dunn GP, Bruce AT, Ikeda H et al (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991–998. https://doi.org/10.1038/ni1102-991

    Article  CAS  PubMed  Google Scholar 

  75. Pagès F, Mlecnik B, Marliot F et al (2018) International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 391:2128–2139. https://doi.org/10.1016/S0140-6736(18)30789-X

    Article  PubMed  Google Scholar 

  76. Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science (80-) 313:1960–1964. https://doi.org/10.1126/science.1129139

    Article  CAS  Google Scholar 

  77. Burke B, Giannoudis A, Corke KP et al (2003) Hypoxia-induced gene expression in human macrophages. Am J Pathol 163:1233–1243. https://doi.org/10.1016/S0002-9440(10)63483-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Doedens AL, Stockmann C, Rubinstein MP et al (2010) macrophage expression of hypoxia-inducible factor-1 suppresses T-cell function and promotes tumor progression. Cancer Res 70:7465–7475. https://doi.org/10.1158/0008-5472.CAN-10-1439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Movahedi K, Laoui D, Gysemans C et al (2010) Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 70:5728–5739. https://doi.org/10.1158/0008-5472.CAN-09-4672

    Article  CAS  PubMed  Google Scholar 

  80. Cortesi F, Delfanti G, Grilli A et al (2018) Bimodal CD40/Fas-dependent crosstalk between iNKT cells and tumor-associated macrophages impairs prostate cancer progression. Cell Rep 22:3006–3020. https://doi.org/10.1016/j.celrep.2018.02.058

    Article  CAS  PubMed  Google Scholar 

  81. Gordon SR, Maute RL, Dulken BW et al (2017) PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545:495–499. https://doi.org/10.1038/nature22396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Neubert NJ, Schmittnaegel M, Bordry N et al (2018) T cell-induced CSF1 promotes melanoma resistance to PD1 blockade. Sci Transl Med 10:eaan3311. https://doi.org/10.1126/scitranslmed.aan3311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Arlauckas SP, Garris CS, Kohler RH et al (2017) In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med 9:eaal3604. https://doi.org/10.1126/scitranslmed.aal3604

    Article  PubMed  PubMed Central  Google Scholar 

  84. Binnewies M, Roberts EW, Kersten K et al (2018) Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 24:541–550. https://doi.org/10.1038/s41591-018-0014-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. DeNardo DG, Brennan DJ, Rexhepaj E et al (2011) Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1:54–67. https://doi.org/10.1158/2159-8274.CD-10-0028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Dijkgraaf EM, Heusinkveld M, Tummers B et al (2013) Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment. Cancer Res 73:2480–2492. https://doi.org/10.1158/0008-5472.CAN-12-3542

    Article  CAS  PubMed  Google Scholar 

  87. Jinushi M, Chiba S, Yoshiyama H et al (2011) Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc Natl Acad Sci USA 108:12425–12430. https://doi.org/10.1073/pnas.1106645108

    Article  PubMed  PubMed Central  Google Scholar 

  88. Mitchem JB, Brennan DJ, Knolhoff BL et al (2013) Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 73:1128–1141. https://doi.org/10.1158/0008-5472.CAN-12-2731

    Article  CAS  PubMed  Google Scholar 

  89. Tsai C-S, Chen F-H, Wang C-C et al (2007) Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth. Int J Radiat Oncol Biol Phys 68:499–507. https://doi.org/10.1016/j.ijrobp.2007.01.041

    Article  CAS  PubMed  Google Scholar 

  90. Stafford JH, Hirai T, Deng L et al (2016) Colony stimulating factor 1 receptor inhibition delays recurrence of glioblastoma after radiation by altering myeloid cell recruitment and polarization. Neuro Oncol 18:797–806. https://doi.org/10.1093/neuonc/nov272

    Article  CAS  PubMed  Google Scholar 

  91. Kalbasi A, Komar C, Tooker GM et al (2017) Tumor-derived CCL2 mediates resistance to radiotherapy in pancreatic ductal adenocarcinoma. Clin Cancer Res 23:137–148. https://doi.org/10.1158/1078-0432.CCR-16-0870

    Article  CAS  PubMed  Google Scholar 

  92. Meng Y, Beckett MA, Liang H et al (2010) Blockade of tumor necrosis factor alpha signaling in tumor-associated macrophages as a radiosensitizing strategy. Cancer Res 70:1534–1543. https://doi.org/10.1158/0008-5472.CAN-09-2995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kioi M, Vogel H, Schultz G et al (2010) Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest 120:694–705. https://doi.org/10.1172/JCI40283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kozin SV, Kamoun WS, Huang Y et al (2010) Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation. Cancer Res 70:5679–5685. https://doi.org/10.1158/0008-5472.CAN-09-4446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kaplan RN, Riba RD, Zacharoulis S et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827. https://doi.org/10.1038/nature04186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Erler JT, Bennewith KL, Cox TR et al (2009) Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15:35–44. https://doi.org/10.1016/j.ccr.2008.11.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Hiratsuka S, Duda DG, Huang Y et al (2011) C-X-C receptor type 4 promotes metastasis by activating p38 mitogen-activated protein kinase in myeloid differentiation antigen (Gr-1)-positive cells. Proc Natl Acad Sci 108:302–307. https://doi.org/10.1073/pnas.1016917108

    Article  PubMed  Google Scholar 

  98. Kitamura T, Doughty-Shenton D, Cassetta L et al (2017) Monocytes differentiate to immune suppressive precursors of metastasis-associated macrophages in mouse models of metastatic breast cancer. Front Immunol 8:2004. https://doi.org/10.3389/fimmu.2017.02004

    Article  CAS  PubMed  Google Scholar 

  99. Celus W, Di Conza G, Oliveira AI et al (2017) Loss of caveolin-1 in metastasis-associated macrophages drives lung metastatic growth through increased angiogenesis. Cell Rep 21:2842–2854. https://doi.org/10.1016/j.celrep.2017.11.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Qian B-Z, Zhang H, Li J et al (2015) FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis. J Exp Med 212:1433–1448. https://doi.org/10.1084/jem.20141555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Qian B, Deng Y, Im JH et al (2009) A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One 4:e6562. https://doi.org/10.1371/journal.pone.0006562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Qian B-Z, Li J, Zhang H et al (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475:222–225. https://doi.org/10.1038/nature10138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kitamura T, Qian B-Z, Soong D et al (2015) CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J Exp Med 212:1043–1059. https://doi.org/10.1084/jem.20141836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Headley MB, Bins A, Nip A et al (2016) Visualization of immediate immune responses to pioneer metastatic cells in the lung. Nature 531:513–517. https://doi.org/10.1038/nature16985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Quail DF, Joyce JA (2017) Molecular pathways: deciphering mechanisms of resistance to macrophage-targeted therapies. Clin Cancer Res 23:876–884. https://doi.org/10.1158/1078-0432.CCR-16-0133

    Article  CAS  PubMed  Google Scholar 

  106. Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41:49–61. https://doi.org/10.1016/j.immuni.2014.06.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zhu Y, Knolhoff BL, Meyer MA et al (2014) CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 74:5057–5069. https://doi.org/10.1158/0008-5472.CAN-13-3723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Pyonteck SM, Akkari L, Schuhmacher AJ et al (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19:1264–1272. https://doi.org/10.1038/nm.3337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Peyraud F, Cousin S, Italiano A (2017) CSF-1R inhibitor development: current clinical status. Curr Oncol Rep 19:70. https://doi.org/10.1007/s11912-017-0634-1

    Article  CAS  PubMed  Google Scholar 

  110. Quail DF, Bowman RL, Akkari L et al (2016) The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science (80-) 352:aad3018. https://doi.org/10.1126/science.aad3018

    Article  CAS  Google Scholar 

  111. Kumar V, Donthireddy L, Marvel D et al (2017) Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC Infiltration of tumors. Cancer Cell 32:654.e5–668.e5. https://doi.org/10.1016/j.ccell.2017.10.005

    Article  CAS  Google Scholar 

  112. Loberg RD, Ying C, Craig M et al (2007) Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. Cancer Res 67:9417–9424. https://doi.org/10.1158/0008-5472.CAN-07-1286

    Article  CAS  PubMed  Google Scholar 

  113. Brana I, Calles A, LoRusso PM et al (2015) Carlumab, an anti-C-C chemokine ligand 2 monoclonal antibody, in combination with four chemotherapy regimens for the treatment of patients with solid tumors: an open-label, multicenter phase 1b study. Target Oncol 10:111–123. https://doi.org/10.1007/s11523-014-0320-2

    Article  PubMed  Google Scholar 

  114. Sandhu SK, Papadopoulos K, Fong PC et al (2013) A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors. Cancer Chemother Pharmacol 71:1041–1050. https://doi.org/10.1007/s00280-013-2099-8

    Article  CAS  PubMed  Google Scholar 

  115. Bonapace L, Coissieux M-M, Wyckoff J et al (2014) Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature 515:130–133. https://doi.org/10.1038/nature13862

    Article  CAS  PubMed  Google Scholar 

  116. D’Incalci M, Badri N, Galmarini CM, Allavena P (2014) Trabectedin, a drug acting on both cancer cells and the tumour microenvironment. Br J Cancer 111:646–650. https://doi.org/10.1038/bjc.2014.149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Guerriero JL (2018) Macrophages: the road less traveled, changing anticancer therapy. Trends Mol Med 24:472–489. https://doi.org/10.1016/j.molmed.2018.03.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Beatty GL, Chiorean EG, Fishman MP et al (2011) CD40 Agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science (80-) 331:1612–1616. https://doi.org/10.1126/science.1198443

    Article  CAS  Google Scholar 

  119. Beatty GL, Li Y, Long KB (2017) Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists. Expert Rev Anticancer Ther 17:175–186. https://doi.org/10.1080/14737140.2017.1270208

    Article  CAS  PubMed  Google Scholar 

  120. Folkes AS, Feng M, Zain JM et al (2018) Targeting CD47 as a cancer therapeutic strategy. Curr Opin Oncol. https://doi.org/10.1097/cco.0000000000000468

    Article  PubMed  PubMed Central  Google Scholar 

  121. Willingham SB, Volkmer J-P, Gentles AJ et al (2012) The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci 109:6662–6667. https://doi.org/10.1073/pnas.1121623109

    Article  PubMed  PubMed Central  Google Scholar 

  122. Guerriero JL, Sotayo A, Ponichtera HE et al (2017) Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature 543:428–432. https://doi.org/10.1038/nature21409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Poh AR, Ernst M (2018) Targeting macrophages in cancer: from bench to bedside. Front Oncol 8:49. https://doi.org/10.3389/fonc.2018.00049

    Article  PubMed  PubMed Central  Google Scholar 

  124. Le RQ, Li L, Yuan W et al (2018) FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T Cell-induced severe or life-threatening cytokine release syndrome. Oncologist 23:943–947. https://doi.org/10.1634/theoncologist.2018-0028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Daei Farshchi Adli A, Jahanban-Esfahlan R, Seidi K et al (2018) An overview on Vadimezan (DMXAA): the vascular disrupting agent. Chem Biol Drug Des 91:996–1006. https://doi.org/10.1111/cbdd.13166

    Article  CAS  PubMed  Google Scholar 

  126. Cheng B, Yuan W-E, Su J et al (2018) Recent advances in small molecule based cancer immunotherapy. Eur J Med Chem 157:582–598. https://doi.org/10.1016/j.ejmech.2018.08.028

    Article  CAS  PubMed  Google Scholar 

  127. Peterson TE, Kirkpatrick ND, Huang Y et al (2016) Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc Natl Acad Sci USA 113:4470–4475. https://doi.org/10.1073/pnas.1525349113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Hans Prenen is a Senior Clinical investigator of the Belgian Foundation against Cancer. This study was funded by H2020 European Research Council (Grant nos. OxyMO, 308459).

Author information

Authors and Affiliations

  1. Oncology Department, University Hospital Antwerp, Edegem, Belgium

    Hans Prenen

  2. Center for Oncological Research, Antwerp University, Edegem, Belgium

    Hans Prenen

  3. Lab of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, 3000, Leuven, Belgium

    Massimiliano Mazzone

  4. Lab of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of oncology, KU Leuven, 3000, Leuven, Belgium

    Massimiliano Mazzone

Authors
  1. Hans Prenen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Massimiliano Mazzone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hans Prenen or Massimiliano Mazzone.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Prenen, H., Mazzone, M. Tumor-associated macrophages: a short compendium. Cell. Mol. Life Sci. 76, 1447–1458 (2019). https://doi.org/10.1007/s00018-018-2997-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-018-2997-3

Keywords

Search

Navigation