Tumor-associated macrophages: a short compendium
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.
Keywords
Monocytes TAM Macrophage Cancer Innate and adaptive immunityNotes
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).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 23:549–555CrossRefGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Biswas SK, Sica A, Lewis CE (2008) Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. J Immunol 180:2011–2017CrossRefGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444. https://doi.org/10.1038/nature07205 CrossRefGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 54:5273–5279PubMedGoogle Scholar
- 30.Minet E, Arnould T, Michel G et al (2000) ERK activation upon hypoxia: involvement in HIF-1 activation. FEBS Lett 468:53–58CrossRefGoogle 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410. https://doi.org/10.1038/nrc1093 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefGoogle 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 CrossRefPubMedGoogle 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 171:2637–2643CrossRefGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle Scholar
- 55.Mantovani A (2010) Molecular pathways linking inflammation and cancer. Curr Mol Med 10:369–373CrossRefGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 15:290–298CrossRefGoogle 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 95:548–553CrossRefGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle Scholar
- 64.Yuan L, Moyon D, Pardanaud L et al (2002) Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 129:4797–4806PubMedGoogle Scholar
- 65.Christiansen A, Detmar M (2011) Lymphangiogenesis and cancer. Genes Cancer 2:1146–1158. https://doi.org/10.1177/1947601911423028 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 72.Thomas L (1982) On immunosurveillance in human cancer. Yale J Biol Med 55:329–333PubMedPubMedCentralGoogle Scholar
- 73.Prehn RT, Main JM (1957) Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst 18:769–778PubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle Scholar