Models for Monocytic Cells in the Tumor Microenvironment

  • Sharon W. L. Lee
  • Giulia Adriani
  • Roger D. KammEmail author
  • Mark R. GillrieEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1224)


Monocytes (Mos) are immune cells that critically regulate cancer, enabling tumor growth and modulating metastasis. Mos can give rise to tumor-associated macrophages (TAMs) and Mo-derived dendritic cells (moDCs), all of which shape the tumor microenvironment (TME). Thus, understanding their roles in the TME is key for improved immunotherapy. Concurrently, various biological and mechanical factors including changes in local cytokines, extracellular matrix production, and metabolic changes in the TME affect the roles of monocytic cells. As such, relevant TME models are critical to achieve meaningful insight on the precise functions, mechanisms, and effects of monocytic cells. Notably, murine models have yielded significant insight into human Mo biology. However, many of these results have yet to be confirmed in humans, reinforcing the need for improved in vitro human TME models for the development of cancer interventions. Thus, this chapter (1) summarizes current insight on the tumor biology of Mos, TAMs, and moDCs, (2) highlights key therapeutic applications relevant to these cells, and (3) discusses various TME models to study their TME-related activity. We conclude with a perspective on the future research trajectory of this topic.


Monocytes Macrophages Monocyte-derived dendritic cells Ontogeny Differentiation and commitment Heterogeneity Cancer 2D versus 3D Human versus mouse Microfluidic models Organ-on-a-chip Tumor microenvironment Combinational immunotherapy Autologous cell therapy Personalized precision medicine 


  1. 1.
    Yona S, Kim K-W, Wolf Y et al (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38:79–91. Scholar
  2. 2.
    Kawamura S, Onai N, Miya F et al (2017) Identification of a human clonogenic progenitor with strict monocyte differentiation potential: a counterpart of mouse cMoPs. Immunity 46:835–848.e4. Scholar
  3. 3.
    Geissmann F, Manz MG, Jung S et al (2018) Development of monocytes, macrophages, and dendritic cells. Sci Rep 8:8868. Scholar
  4. 4.
    Auffray C, Sieweke MH, Geissmann F (2009) Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 27:669–692. Scholar
  5. 5.
    Zhu YP, Thomas GD, Hedrick CC (2016) Jeffrey M. Hoeg award lecture: transcriptional control of monocyte development. Arterioscler Thromb Vasc Biol 36:1722–1733. Scholar
  6. 6.
    Kurotaki D, Yamamoto M, Nishiyama A et al (2014) IRF8 inhibits C/EBPα activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils. Nat Commun 5:4978. Scholar
  7. 7.
    Kurotaki D, Osato N, Nishiyama A et al (2013) Essential role of the IRF8-KLF4 transcription factor cascade in murine monocyte differentiation. Blood 121:1839–1849. Scholar
  8. 8.
    Lee J, Breton G, Oliveira TYK et al (2015) Restricted dendritic cell and monocyte progenitors in human cord blood and bone marrow. J Exp Med 212:385–399. Scholar
  9. 9.
    Yáñez A, Coetzee SG, Olsson A et al (2017) Granulocyte-monocyte progenitors and monocyte-dendritic cell progenitors independently produce functionally distinct monocytes. Immunity 47:890–902.e4. Scholar
  10. 10.
    Oetjen KA, Lindblad KE, Goswami M et al (2018) Human bone marrow assessment by single-cell RNA sequencing, mass cytometry, and flow cytometry. JCI Insight 3:e124928. Scholar
  11. 11.
    Guilliams M, Ginhoux F, Jakubzick C et al (2014) Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol 14:571. Scholar
  12. 12.
    Chen Z, Feng X, Herting CJ et al (2017) Cellular and molecular identity of tumor-associated macrophages in glioblastoma. Cancer Res 77:2266–2278. Scholar
  13. 13.
    Fogg DK, Sibon C, Miled C et al (2006) A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311:83–87. Scholar
  14. 14.
    Wiktor-Jedrzejczak W, Ahmed A, Szczylik C, Skelly RR (2004) Hematological characterization of congenital osteopetrosis in op/op mouse. Possible mechanism for abnormal macrophage differentiation. J Exp Med 156:1516–1527. Scholar
  15. 15.
    Valledor AF, Borràs FE, Cullell-Young M, Celada A (1998) Transcription factors that regulate monocyte/macrophage differentiation. J Leukoc Biol 63:405–417. Scholar
  16. 16.
    Richards DM, Hettinger J, Feuerer M (2013) Monocytes and macrophages in cancer: development and functions. Cancer Microenviron 6:179–191. Scholar
  17. 17.
    Franklin RA, Li MO (2014) The ontogeny of tumor-associated macrophages: a new understanding of cancer-elicited inflammation. Oncoimmunology 3:e955346. Scholar
  18. 18.
    Yang M, McKay D, Pollard JW, Lewis CE (2018) Diverse functions of macrophages in different tumor microenvironments. Cancer Res 78:5492–5503. Scholar
  19. 19.
    Passlick B, Flieger D, Ziegler-Heitbrock HW (1989) Identification and characterization of a novel monocyte subpopulation in human peripheral blood. Blood 74:2527–2534CrossRefGoogle Scholar
  20. 20.
    Weiner LM, Li W, Holmes M et al (1994) Phase I trial of recombinant macrophage colony-stimulating factor and recombinant γ-interferon: toxicity, monocytosis, and clinical effects. Cancer Res 54:4084–4090PubMedGoogle Scholar
  21. 21.
    Sunderkötter C, Nikolic T, Dillon MJ et al (2004) Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Immunol 172:4410–4417. Scholar
  22. 22.
    Patel AA, Zhang Y, Fullerton JN et al (2017) The fate and lifespan of human monocyte subsets in steady state and systemic inflammation. J Exp Med 214:1913–1923. Scholar
  23. 23.
    Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:71–82. Scholar
  24. 24.
    Weber C, Belge KU, Von Hundelshausen P et al (2000) Differential chemokine receptor expression and function in human monocyte subpopulations. J Leukoc Biol 67:699–704. Scholar
  25. 25.
    Palframan RT, Jung S, Cheng G et al (2002) Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissue. J Exp Med 194:1361–1374. Scholar
  26. 26.
    Clanchy FIL (2006) Detection and properties of the human proliferative monocyte subpopulation. J Leukoc Biol 79:757–766. Scholar
  27. 27.
    Tjew SL, Brown KL, Kannagi R, Johnson P (2005) Expression of N-acetylglucosamine 6-O-sulfotransferases (GlcNAc6STs)-1 and -4 in human monocytes: GlcNAc6ST-1 is implicated in the generation of the 6-sulfo N-acetyllactosamine/Lewis x epitope on CD44 and is induced by TNF-alpha. Glycobiology 15:7–13. Scholar
  28. 28.
    De Baey A, Mende I, Riethmueller G, Baeuerle PA (2001) Phenotype and function of human dendritic cells derived from M-DC8+ monocytes. Eur J Immunol 31:1646–1655.<1646::AID-IMMU1646>3.0.CO;2-XCrossRefPubMedGoogle Scholar
  29. 29.
    Von Bubnoff D, Fimmers R, Bogdanow M et al (2004) Asymptomatic atopy is associated with increased indoleamine 2,3-dioxygenase activity and interleukin-10 production during seasonal allergen exposure. Clin Exp Allergy 34:1056–1063. Scholar
  30. 30.
    Maurer D (2004) Expression of functional high affinity immunoglobulin E receptors (Fc epsilon RI) on monocytes of atopic individuals. J Exp Med 179:745–750. Scholar
  31. 31.
    Ziegler-Heitbrock L, Hofer TPJ (2013) Toward a refined definition of monocyte subsets. Front Immunol 4:1–5. Scholar
  32. 32.
    Thomas GD, Hamers AAJ, Nakao C et al (2017) Human blood monocyte subsets. Arterioscler Thromb Vasc Biol 37:1548–1558. Scholar
  33. 33.
    Villani AC, Satija R, Reynolds G et al (2017) Single-cell RNA-Seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science 356:eaah4573. Scholar
  34. 34.
    Schauer D, Starlinger P, Reiter C et al (2012) Intermediate monocytes but not TIE2-expressing monocytes are a sensitive diagnostic indicator for colorectal cancer. PLoS One 7:e44450. Scholar
  35. 35.
    Cros J, Cagnard N, Woollard K et al (2010) Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 33:375–386. Scholar
  36. 36.
    Goudot C, Coillard A, Villani AC et al (2017) Aryl hydrocarbon receptor controls monocyte differentiation into dendritic cells versus macrophages. Immunity 47:582–596.e6. Scholar
  37. 37.
    Jakubzick C, Gautier EL, Gibbings SL et al (2013) Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity 39:599–610. Scholar
  38. 38.
    Auffray C, Fogg D, Garfa M et al (2007) Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317:66–670. Scholar
  39. 39.
    Carlin LM, Stamatiades EG, Auffray C et al (2013) Nr4a1-dependent Ly6Clow monocytes monitor endothelial cells and orchestrate their disposal. Cell 153:362–375. Scholar
  40. 40.
    Jakubzick CV, Randolph GJ, Henson PM (2017) Monocyte differentiation and antigen-presenting functions. Nat Rev Immunol 17:349–362. Scholar
  41. 41.
    Serbina NV, Pamer EG (2006) Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol 7:311–317. Scholar
  42. 42.
    Olingy CE, Dinh HQ, Hedrick CC (2019) Monocyte heterogeneity and functions in cancer. J Leukoc Biol 106:309–322. Scholar
  43. 43.
    Misharin AV, Cuda CM, Saber R et al (2014) Nonclassical Ly6C- monocytes drive the development of inflammatory arthritis in mice. Cell Rep 9:591–604. Scholar
  44. 44.
    Olingy CE, San Emeterio CL, Ogle ME et al (2017) Non-classical monocytes are biased progenitors of wound healing macrophages during soft tissue injury. Sci Rep 7:447. Scholar
  45. 45.
    Hanna RN, Cekic C, Sag D et al (2015) Patrolling monocytes control tumor metastasis to the lung. Science 350:985–990. Scholar
  46. 46.
    Cassetta L, Pollard JW (2016) Cancer immunosurveillance: role of patrolling monocytes. Cell Res 26:3–4. Scholar
  47. 47.
    Ziegler-Heitbrock L, Ancuta P, Crowe S et al (2010) Nomenclature of monocytes and dendritic cells in blood. Blood 116:e74–e80. Scholar
  48. 48.
    Ingersoll MA, Spanbroek R, Lottaz C et al (2009) Comparison of gene expression profiles between human and mouse monocyte subsets. Blood 115:e10–e19. Scholar
  49. 49.
    Locati M, Deuschle U, Massardi ML et al (2014) Analysis of the gene expression profile activated by the CC chemokine ligand 5/RANTES and by lipopolysaccharide in human monocytes. J Immunol 168:3557–3562. Scholar
  50. 50.
    Franklin RA, Liao W, Sarkar A et al (2014) The cellular and molecular origin of tumor-associated macrophages. Science 344:921–925. Scholar
  51. 51.
    Movahedi K, Guilliams M, Van Den Bossche J et al (2008) Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell suppressive activity. Blood 111:4233–4244. Scholar
  52. 52.
    Kitamura T, Doughty-Shenton D, Cassetta L et al (2018) Monocytes differentiate to immune suppressive precursors of metastasis-associated macrophages in mouse models of metastatic breast cancer. Front Immunol 8:2004. Scholar
  53. 53.
    Qian BZ, Li J, Zhang H et al (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475:222–225. Scholar
  54. 54.
    Chun E, Lavoie S, Michaud M et al (2015) CCL2 promotes colorectal carcinogenesis by enhancing polymorphonuclear myeloid-derived suppressor cell population and function. Cell Rep 12:244–257. Scholar
  55. 55.
    Murdoch C, Giannoudis A, Lewis CE (2004) Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 104:2224–2234. Scholar
  56. 56.
    Lee HW, Choi HJ, Ha SJ et al (2013) Recruitment of monocytes/macrophages in different tumor microenvironments. Biochim Biophys Acta Rev Cancer 1835:170–179. Scholar
  57. 57.
    Schlesinger M, Bendas G (2015) Vascular cell adhesion molecule-1 (VCAM-1)—an increasing insight into its role in tumorigenicity and metastasis. Int J Cancer 136:2504–2514. Scholar
  58. 58.
    Kong DH, Kim YK, Kim MR et al (2018) Emerging roles of vascular cell adhesion molecule-1 (VCAM-1) in immunological disorders and cancer. Int J Mol Sci 19:E1057. Scholar
  59. 59.
    Shand FHW, Ueha S, Otsuji M et al (2014) Tracking of intertissue migration reveals the origins of tumor-infiltrating monocytes. Proc Natl Acad Sci 111:7771–7776. Scholar
  60. 60.
    Zhao H, Wang J, Kong X et al (2016) CD47 promotes tumor invasion and metastasis in non-small cell lung cancer. Sci Rep 6:29719. Scholar
  61. 61.
    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 U S A 109:6662–6667. Scholar
  62. 62.
    Kubo H, Mensurado S, Gonçalves-Sousa N et al (2017) Primary tumors limit metastasis formation through induction of IL15-mediated cross-talk between patrolling monocytes and NK cells. Cancer Immunol Res 5:812–820. Scholar
  63. 63.
    Gordon IO, Freedman RS (2006) Defective antitumor function of monocyte-derived macrophages from epithelial ovarian cancer patients. Clin Cancer Res 12:1515–1524. Scholar
  64. 64.
    Yeap WH, Wong KL, Shimasaki N et al (2016) CD16 is indispensable for antibody-dependent cellular cytotoxicity by human monocytes. Sci Rep 6:34310. Scholar
  65. 65.
    Schmitz M, Zhao S, Schakel K et al (2002) Native human blood dendritic cells as potent effectors in antibody-dependent cellular cytotoxicity. Blood 100:1502–1504CrossRefGoogle Scholar
  66. 66.
    Elavazhagan S, Fatehchand K, Santhanam V et al (2015) Granzyme B expression is enhanced in human monocytes by TLR8 agonists and contributes to antibody-dependent cellular cytotoxicity. J Immunol 194:2786–2795. Scholar
  67. 67.
    Griffith TS, Wiley SR, Kubin MZ et al (2002) Monocyte-mediated tumoricidal activity via the tumor necrosis factor-related cytokine, TRAIL. J Exp Med 189:1343–1354. Scholar
  68. 68.
    Jaiswal S, Jamieson CHM, Pang WW et al (2009) CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138:271–285. Scholar
  69. 69.
    Chao MP, Alizadeh AA, Tang C et al (2010) Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142:699–713. Scholar
  70. 70.
    Hartwig T, Montinaro A, von Karstedt S et al (2017) The TRAIL-induced cancer secretome promotes a tumor-supportive immune microenvironment via CCR2. Mol Cell 65:730–742.e5. Scholar
  71. 71.
    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. Scholar
  72. 72.
    Benito-Martin A, Di Giannatale A, Ceder S, Peinado H (2015) The new deal: a potential role for secreted vesicles in innate immunity and tumor progression. Front Immunol 6:1–13. Scholar
  73. 73.
    Chalmin F, Ladoire S, Mignot G et al (2010) Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest 120:457–471. Scholar
  74. 74.
    Lee Y, Chittezhath M, André V et al (2012) Protumoral role of monocytes in human B-cell precursor acute lymphoblastic leukemia: involvement of the chemokine CXCL10. Blood 119:227–237. Scholar
  75. 75.
    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. Scholar
  76. 76.
    Mantovani A, Marchesi F, Malesci A et al (2017) Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14:399–416. Scholar
  77. 77.
    Tiemessen MM, Jagger AL, Evans HG et al (2007) CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci 104:19446–19451. Scholar
  78. 78.
    Azizi E, Carr AJ, Plitas G et al (2018) Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell 174:1293–1308. Scholar
  79. 79.
    Varol C, Landsman L, Fogg DK et al (2006) Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J Exp Med 204:171–180. Scholar
  80. 80.
    Bogunovic M, Ginhoux F, Helft J et al (2009) Origin of the lamina propria dendritic cell network. Immunity 31:513–525. Scholar
  81. 81.
    Bain CC, Mowat AMI (2014) The monocyte-macrophage axis in the intestine. Cell Immunol 291:41–48. Scholar
  82. 82.
    Allavena P, Sica A, Solinas G et al (2008) The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol 66:1–9. Scholar
  83. 83.
    Loyher P-L, Hamon P, Laviron M et al (2018) Macrophages of distinct origins contribute to tumor development in the lung. J Exp Med 215:2536–2553. Scholar
  84. 84.
    Lu H, Clauser KR, Tam WL et al (2014) A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol 16:1105–1117. Scholar
  85. 85.
    Arwert EN, Harney AS, Entenberg D et al (2018) A unidirectional transition from migratory to perivascular macrophage is required for tumor cell intravasation. Cell Rep 23:1239–1248. Scholar
  86. 86.
    Lapenna A, De Palma M, Lewis CE (2018) Perivascular macrophages in health and disease. Nat Rev Immunol 18:689–702. Scholar
  87. 87.
    Kuang D-M, Zhao Q, Peng C et al (2009) Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med 206:1327–1337. Scholar
  88. 88.
    Lee SWL, Adriani G, Ceccarello E et al (2018) Characterizing the role of monocytes in T cell cancer immunotherapy using a 3D microfluidic model. Front Immunol 9:416. Scholar
  89. 89.
    Shimizu K, Iyoda T, Okada M et al (2018) Immune suppression and reversal of the suppressive tumor microenvironment. Int Immunol 30:445–455. Scholar
  90. 90.
    Ruffell B, Chang-Strachan D, Chan V et al (2014) 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. Scholar
  91. 91.
    Aras S, Raza Zaidi M (2017) TAMeless traitors: macrophages in cancer progression and metastasis. Br J Cancer 117:1583–1591. Scholar
  92. 92.
    Forssell J, Öberg Å, Henriksson ML et al (2007) High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res 13:1472–1479. Scholar
  93. 93.
    Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41:49–61. Scholar
  94. 94.
    Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795. Scholar
  95. 95.
    Gordon S (2003) Alternative activation of macrophage by IL-10. Nat Rev Immunol 3:23. Scholar
  96. 96.
    Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969. Scholar
  97. 97.
    Singhal S, Stadanlick J, Annunziata MJ et al (2019) Human tumor-associated monocytes/macrophages and their regulation of T cell responses in early-stage lung cancer. Sci Transl Med 11:eaat1500. Scholar
  98. 98.
    Zhu Y, Herndon JM, Sojka DK et al (2017) Tissue resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47:323–338. Scholar
  99. 99.
    Penny HL, Sieow JL, Adriani G et al (2016) Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma. Oncoimmunology 5:1–15. Scholar
  100. 100.
    Qian B-Z, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51. Scholar
  101. 101.
    Pyonteck SM, Gardner EE, Gutin PH et al (2016) Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies. Cell Rep 17:2445–2459. Scholar
  102. 102.
    Mills CD, Kincaid K, Alt JM et al (2000) M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 164:6166–6173. Scholar
  103. 103.
    Gautier EL, Shay T, Miller J et al (2012) Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 13:1118–1128. Scholar
  104. 104.
    Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496:445–455. Scholar
  105. 105.
    Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964. Scholar
  106. 106.
    Broz ML, Binnewies M, Boldajipour B et al (2014) Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26:638–652. Scholar
  107. 107.
    Kuhn S, Yang J, Ronchese F (2015) Monocyte-derived dendritic cells are essential for CD8+ T cell activation and antitumor responses after local immunotherapy. Front Immunol 6:1–14. Scholar
  108. 108.
    Engblom C, Pfirschke C, Pittet MJ (2016) The role of myeloid cells in cancer therapies. Nat Rev Cancer 16:447–462. Scholar
  109. 109.
    Mildner A, Jung S (2014) Development and function of dendritic cell subsets. Immunity 40:642–656. Scholar
  110. 110.
    Miller JC, Brown BD, Shay T et al (2012) Deciphering the transcriptional network of the dendritic cell lineage. Nat Immunol 13:888–899. Scholar
  111. 111.
    Tamoutounour S, Henri S, Lelouard H et al (2012) CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1-inducing role of mesenteric lymph node macrophages during colitis. Eur J Immunol 42:3150–3166. Scholar
  112. 112.
    Plantinga M, Guilliams M, Vanheerswynghels M et al (2013) Conventional and monocyte-derived CD11b + dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity 38:322–335. Scholar
  113. 113.
    Gubin MM, Esaulova E, Ward JP et al (2018) High-dimensional analysis delineates myeloid and lymphoid compartment remodeling during successful immune-checkpoint cancer therapy. Cell 175:1014–1030.e19. Scholar
  114. 114.
    Santini SM, Lapenta C, Logozzi M et al (2002) Type I interferon as a powerful adjuvant for monocyte-derived dendritic cell development and activity in vitro and in Hu-PBL-SCID mice. J Exp Med 191:1777–1788. Scholar
  115. 115.
    Vanderheyde N, Aksoy E, Amraoui Z et al (2014) Tumoricidal activity of monocyte-derived dendritic cells: evidence for a Caspase-8-dependent, Fas-associated death domain-independent mechanism. J Immunol 167:3565–3569. Scholar
  116. 116.
    Sharma MD, Rodriguez PC, Koehn BH et al (2018) Activation of p53 in immature myeloid precursor cells controls differentiation into Ly6c+ CD103+ monocytic antigen-presenting cells in tumors. Immunity 48:91–106.e6. Scholar
  117. 117.
    Serbina NV, Salazar-Mather TP, Biron CA et al (2003) TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19:59–70. Scholar
  118. 118.
    Mildner A, Yona S, Jung S (2013) A close encounter of the third kind: monocyte-derived cells. Adv Immunol 120:69–103CrossRefGoogle Scholar
  119. 119.
    Segura E, Amigorena S (2013) Inflammatory dendritic cells in mice and humans. Trends Immunol 34:440–445. Scholar
  120. 120.
    Xu Y, Zhan Y, Lew AM et al (2007) Differential development of murine dendritic cells by GM-CSF versus Flt3 ligand has implications for inflammation and trafficking. J Immunol 179:7577–7584. Scholar
  121. 121.
    Lu P, Weaver VM, Werb Z (2012) The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 196:395–406. Scholar
  122. 122.
    Huleihel L, Dziki JL, Bartolacci JG et al (2017) Macrophage phenotype in response to ECM bioscaffolds. Semin Immunol 29:2–13. Scholar
  123. 123.
    Kim H, Cha J, Jang M, Kim P (2019) Hyaluronic acid-based extracellular matrix triggers spontaneous M2-like polarity of monocyte/macrophage. Biomater Sci 7:2264–2271. Scholar
  124. 124.
    Walker C, Mojares E, del Río Hernández A (2018) Role of extracellular matrix in development and cancer progression. Int J Mol Sci 19:3028. Scholar
  125. 125.
    Porrello A, Leslie PL, Harrison EB et al (2018) Factor XIIIA-expressing inflammatory monocytes promote lung squamous cancer through fibrin cross-linking. Nat Commun 9:1988. Scholar
  126. 126.
    Madsen DH, Jürgensen HJ, Siersbæk MS et al (2017) Tumor-associated macrophages derived from circulating inflammatory monocytes degrade collagen through cellular uptake. Cell Rep 21:3662–3671. Scholar
  127. 127.
    Opdenakker G, Van Damme J (1992) Chemotactic factors, passive invasion and metastasis of cancer cells. Immunol Today 13:463–464. Scholar
  128. 128.
    Wyckoff JB, Wang Y, Lin EY et al (2007) Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67:2649–2656. Scholar
  129. 129.
    Wyckoff J, Wang W, Lin EY et al (2004) A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 64:7022–7029. Scholar
  130. 130.
    Li R, Hebert JD, Lee TA et al (2016) Macrophage-secreted TNFa and TGFb1 influence migration speed and persistence of cancer cells in 3D tissue culture via independent pathways. Cancer Res 77:279–290. Scholar
  131. 131.
    Bai J, Adriani G, Dang TM et al (2015) Contact-dependent carcinoma aggregate dispersion by M2a macrophages via ICAM-1 and β2 integrin interactions. Oncotarget 6:25295–25307. Scholar
  132. 132.
    Gocheva V, Wang HW, Gadea BB et al (2010) IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev 24:241–255. Scholar
  133. 133.
    Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161–174. Scholar
  134. 134.
    Martinez FO, Helming L, Gordon S (2009) Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27:451–483. Scholar
  135. 135.
    Minutti CM, Knipper JA, Allen JE, Zaiss DMW (2017) Tissue-specific contribution of macrophages to wound healing. Semin Cell Dev Biol 61:3–11. Scholar
  136. 136.
    Afik R, Zigmond E, Vugman M et al (2016) Tumor macrophages are pivotal constructors of tumor collagenous matrix. J Exp Med 213:2315–2331. Scholar
  137. 137.
    Shankavaram UT, Lai WC, Netzel-Arnett S et al (2001) Monocyte membrane type 1-matrix metalloproteinase: prostaglandin-dependent regulation and role in metalloproteinase-2 activation. J Biol Chem 276:19027–19032. Scholar
  138. 138.
    Ho HH, Antoniv TT, Ji J-D, Ivashkiv LB (2014) Lipopolysaccharide-induced expression of matrix metalloproteinases in human monocytes is suppressed by IFN-γ via superinduction of ATF-3 and suppression of AP-1. J Immunol 181:5089–5097. Scholar
  139. 139.
    Davis GE, Senger DR (2005) Endothelial extracellular matrix. Circ Res 97:1093–1107. Scholar
  140. 140.
    Coffelt SB, Tal AO, Scholz A et al (2010) Angiopoietin-2 regulates gene expression in TIE2-expressing monocytes and augments their inherent proangiogenic functions. Cancer Res 70:5270–5280. Scholar
  141. 141.
    Avraamides CJ, Garmy-Susini B, Varner JA (2008) Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 8:604–617. Scholar
  142. 142.
    Zeisberger SM, Odermatt B, Marty C et al (2006) Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer 95:272–281. Scholar
  143. 143.
    Rivera LB, Bergers G (2015) Intertwined regulation of angiogenesis and immunity by myeloid cells. Trends Immunol 36:240–249. Scholar
  144. 144.
    Riabov V, Gudima A, Wang N et al (2014) Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol 5:1–13. Scholar
  145. 145.
    Waltenberger J, Lange J, Kranz A (2012) Vascular endothelial growth factor-A-induced chemotaxis of monocytes is attenuated in patients with diabetes mellitus. Circulation 102:185–190. Scholar
  146. 146.
    Chittezhath M, Dhillon MK, Lim JY et al (2014) Molecular profiling reveals a tumor-promoting phenotype of monocytes and macrophages in human cancer progression. Immunity 41:815–829. Scholar
  147. 147.
    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. Scholar
  148. 148.
    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. Scholar
  149. 149.
    Ji J, Zhang G, Sun B et al (2013) The frequency of tumor-infiltrating tie-2-expressing monocytes in renal cell carcinoma: its relationship to angiogenesis and progression. Urology 82:974.e9–974.e13. Scholar
  150. 150.
    Harney AS, Arwert EN, Entenberg D et al (2015) Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov 5:932–943. Scholar
  151. 151.
    Sfiligoi C, De Luca A, Cascone I et al (2003) Angiopoietin-2 expression in breast cancer correlates with lymph node invasion and short survival. Int J Cancer 103:466–474. Scholar
  152. 152.
    Augustin HG, Young Koh G, Thurston G, Alitalo K (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin—tie system. Nat Rev Mol Cell Biol 10:165–177. Scholar
  153. 153.
    Venneri MA, De Palma M, Ponzoni M et al (2007) Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer. Blood 109:5276–5285. Scholar
  154. 154.
    Sidibe A, Ropraz P, Jemelin S et al (2018) Angiogenic factor-driven inflammation promotes extravasation of human proangiogenic monocytes to tumours. Nat Commun 9:355. Scholar
  155. 155.
    Zhang W, Zhu XD, Sun HC et al (2010) Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin Cancer Res 16:3420–3430. Scholar
  156. 156.
    Adams DL, Martin SS, Alpaugh RK et al (2014) Circulating giant macrophages as a potential biomarker of solid tumors. Proc Natl Acad Sci 111:3514–3519. Scholar
  157. 157.
    Nielsen SR, Schmid MC (2017) Macrophages as key drivers of cancer progression and metastasis. Mediators Inflamm 2017:1–11. Scholar
  158. 158.
    Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19:1423–1437. Scholar
  159. 159.
    Gil-Bernabé AM, Ferjančič Š, Tlalka M et al (2012) 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. Scholar
  160. 160.
    Cortez-Retamozo V, Etzrodt M, Newton A et al (2012) Origins of tumor-associated macrophages and neutrophils. Proc Natl Acad Sci U S A 109:2491–2496. Scholar
  161. 161.
    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. Scholar
  162. 162.
    Sceneay J, Smyth MJ, Möller A (2013) The pre-metastatic niche: finding common ground. Cancer Metastasis Rev 32:449–464. Scholar
  163. 163.
    Kahlert C, Kalluri R (2013) Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med 91:431–437. Scholar
  164. 164.
    Peinado H, Lavotshkin S, Lyden D (2011) The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 21:139–146. Scholar
  165. 165.
    Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174. Scholar
  166. 166.
    Lesokhin AM, Hohl TM, Kitano S et al (2012) Monocytic CCR2 + myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment. Cancer Res 72:876–886. Scholar
  167. 167.
    Li X, Yao W, Yuan Y et al (2015) Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut 66:157–167. Scholar
  168. 168.
    Hartley G, Faulhaber E, Caldwell A et al (2017) Immune regulation of canine tumour and macrophage PD-L1 expression. Vet Comp Oncol 15:534–549. Scholar
  169. 169.
    Abiko K, Matsumura N, Hamanishi J et al (2015) IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br J Cancer 112:1501–1509. Scholar
  170. 170.
    Gaudino SJ, Kumar P (2019) Cross-talk between antigen presenting cells and T cells impacts intestinal homeostasis, bacterial infections, and tumorigenesis. Front Immunol 10:360. Scholar
  171. 171.
    Sheng J, Chen Q, Soncin I et al (2017) A discrete subset of monocyte-derived cells among typical conventional type 2 dendritic cells can efficiently cross-present. Cell Rep 21:1203–1214. Scholar
  172. 172.
    Tseng D, Volkmer J-P, Willingham SB et al (2013) Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc Natl Acad Sci 110:11103–11108. Scholar
  173. 173.
    Eisel D, Das K, Dickes E et al (2019) Cognate interaction with CD4 + T cells instructs tumor-associated macrophages to acquire M1-like phenotype. Front Immunol 10:219. Scholar
  174. 174.
    Westhorpe CLV, Ursula Norman M, Hall P et al (2018) Effector CD4+ T cells recognize intravascular antigen presented by patrolling monocytes. Nat Commun 9:747. Scholar
  175. 175.
    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. Scholar
  176. 176.
    Sanford DE, Belt BA, Panni RZ et al (2013) Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res 19:3404–3415. Scholar
  177. 177.
    Schlecker E, Stojanovic A, Eisen C et al (2012) Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5-dependent recruitment of regulatory T cells favoring tumor growth. J Immunol 189:5602–5611. Scholar
  178. 178.
    Pommier A, Audemard A, Durand A et al (2013) Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+ T cells. Proc Natl Acad Sci U S A 110:13085–13090. Scholar
  179. 179.
    Romano E, Kusio-Kobialka M, Foukas PG et al (2015) Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci U S A 112:6140–6145. Scholar
  180. 180.
    Lee YY, Choi CH, Sung CO et al (2012) Prognostic value of pre-treatment circulating monocyte count in patients with cervical cancer: comparison with SCC-Ag level. Gynecol Oncol 124:92–97. Scholar
  181. 181.
    Lu Y, Cai Z, Xiao G et al (2007) CCR2 expression correlates with prostate cancer progression. J Cell Biochem 101:676–685. Scholar
  182. 182.
    Topalian S, Hodi F, Brahmer J et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. Scholar
  183. 183.
    Brahmer JR, Tykodi SS, Chow LQ et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465. Scholar
  184. 184.
    Rebelatto MC, Midha A, Mistry A et al (2016) Development of a programmed cell death ligand-1 immunohistochemical assay validated for analysis of non-small cell lung cancer and head and neck squamous cell carcinoma. Diagn Pathol 11:95. Scholar
  185. 185.
    Taube JM, Klein A, Brahmer JR et al (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20:5064–5074. Scholar
  186. 186.
    Garon EB, Rizvi NA, Hui R et al (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018–2046. Scholar
  187. 187.
    Stotz M, Pichler M, Absenger G et al (2014) The preoperative lymphocyte to monocyte ratio predicts clinical outcome in patients with stage III colon cancer. Br J Cancer 110:435–440. Scholar
  188. 188.
    Hu P, Shen H, Wang G et al (2014) Prognostic significance of systemic inflammation-based lymphocyte-monocyte ratio in patients with lung cancer: based on a large cohort study. PLoS One 9:e108062. Scholar
  189. 189.
    Eo WK, Chang HJ, Kwon SH et al (2016) The lymphocyte-monocyte ratio predicts patient survival and aggressiveness of ovarian cancer. J Cancer 7:289–296. Scholar
  190. 190.
    Thorsson V, Gibbs DL, Brown SD et al (2018) The immune landscape of cancer. Immunity 48:812–830.e14. Scholar
  191. 191.
    Rooney MS, Shukla SA, Wu CJ et al (2015) Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160:48–61. Scholar
  192. 192.
    Fridlender ZG, Buchlis G, Kapoor V et al (2010) Microenvironment and immunology CCL2 blockade augments cancer immunotherapy. Cancer Res 70:109–127. Scholar
  193. 193.
    Shojaei F, Wu X, Malik AK et al (2007) Tumor refractoriness to anti-VEGF treatment is mediated by CD11b +Gr1+ myeloid cells. Nat Biotechnol 25:911–920. Scholar
  194. 194.
    Nakashima H, Miyake K, Clark CR et al (2012) Potent antitumor effects of combination therapy with IFNs and monocytes in mouse models of established human ovarian and melanoma tumors. Cancer Immunol Immunother 61:1081–1092. Scholar
  195. 195.
    Linehan D, Noel MS, Hezel AF et al (2018) Overall survival in a trial of orally administered CCR2 inhibitor CCX872 in locally advanced/metastatic pancreatic cancer: correlation with blood monocyte counts. J Clin Oncol 36:92. Scholar
  196. 196.
    Vinogradov S, Warren G, Wei X (2014) Macrophages associated with tumors as potential targets and therapeutic intermediates. Nanomedicine 9:695–707. Scholar
  197. 197.
    Mok S, Koya RC, Tsui C et al (2014) Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy. Cancer Res 74:153–161. Scholar
  198. 198.
    Ries CH, Cannarile MA, Hoves S et al (2014) Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25:846–859. Scholar
  199. 199.
    Tap WD, Wainberg ZA, Anthony SP et al (2015) Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. N Engl J Med 373:428–437. Scholar
  200. 200.
    Cassier PA, Italiano A, Gomez-Roca CA et al (2015) CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study. Lancet Oncol 16:949–956. Scholar
  201. 201.
    Leuschner F, Dutta P, Gorbatov R et al (2011) Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol 29:1005–1010. Scholar
  202. 202.
    Germano G, Frapolli R, Simone M et al (2010) Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res 70:2235–2244. Scholar
  203. 203.
    Germano G, Frapolli R, Belgiovine C et al (2013) Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 23:249–262. Scholar
  204. 204.
    Castro F, Pinto ML, Silva AM et al (2017) Pro-inflammatory chitosan/poly(c-glutamic acid) nanoparticles modulate human antigen-presenting cells phenotype and revert their pro-invasive capacity. Acta Biomater 63:96–109. Scholar
  205. 205.
    Zhu Z, Scalfi-Happ C, Ryabova A et al (2018) Photodynamic activity of Temoporfin nanoparticles induces a shift to the M1-like phenotype in M2-polarized macrophages. J Photochem Photobiol B Biol 185:215–222. Scholar
  206. 206.
    Klug F, Prakash H, Huber PE et al (2013) Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24:589–602. Scholar
  207. 207.
    Quail DF, Bowman RL, Akkari L et al (2016) The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science 352:aad3018. Scholar
  208. 208.
    Kloepper J, Riedemann L, Amoozgar Z et al (2016) Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc Natl Acad Sci U S A 113:4476–4481. Scholar
  209. 209.
    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 U S A 113:4470–4475. Scholar
  210. 210.
    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 331:1612–1616. Scholar
  211. 211.
    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. Scholar
  212. 212.
    Gunderson AJ, Kaneda MM, Tsujikawa T et al (2016) Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov 6:270–285. Scholar
  213. 213.
    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. Scholar
  214. 214.
    Shang N, Figini M, Shangguan J et al (2017) Dendritic cells based immunotherapy. Am J Cancer Res 7:2091–2102PubMedPubMedCentralGoogle Scholar
  215. 215.
    Ghansah T, Vohra N, Kinney K et al (2013) Dendritic cell immunotherapy combined with gemcitabine chemotherapy enhances survival in a murine model of pancreatic carcinoma. Cancer Immunol Immunother 62:1083–1091. Scholar
  216. 216.
    Vo M-C, Nguyen-Pham T-N, Lee H-J et al (2017) Combination therapy with dendritic cells and lenalidomide is an effective approach to enhance antitumor immunity in a mouse colon cancer model. Oncotarget 8:27252–27262. Scholar
  217. 217.
    Jalili A, Makowski M, Świtaj T et al (2004) Effective photoimmunotherapy of murine colon carcinoma induced by the combination of photodynamic therapy and dendritic cells. Clin Cancer Res 10:4498–4508. Scholar
  218. 218.
    van Gulijk M, Dammeijer F, Aerts JGJV, Vroman H (2018) Combination strategies to optimize efficacy of dendritic cell-based immunotherapy. Front Immunol 9:2759. Scholar
  219. 219.
    Green DS, Nunes AT, Tosh KW et al (2019) Production of a cellular product consisting of monocytes stimulated with Sylatron® (Peginterferon alfa-2b) and Actimmune® (Interferon gamma-1b) for human use. J Transl Med 17:82. Scholar
  220. 220.
    Baron-Bodo V, Doceur P, Lefebvre ML et al (2005) Anti-tumor properties of human-activated macrophages produced in large scale for clinical application. Immunobiology 210:267–277. Scholar
  221. 221.
    Strasser EF, Eckstein R (2010) Optimization of leukocyte collection and monocyte isolation for dendritic cell culture. Transfus Med Rev 24:130–139. Scholar
  222. 222.
    Faradji A, Bohbot A, Frost H et al (1991) Phase I study of liposomal MTP-PE-activated autologous monocytes administered intraperitoneally to patients with peritoneal carcinomatosis. J Clin Oncol 9:1251–1260. Scholar
  223. 223.
    Green DS, Nunes AT, David-Ocampo V et al (2018) A Phase 1 trial of autologous monocytes stimulated ex vivo with Sylatron® (Peginterferon alfa-2b) and Actimmune® (Interferon gamma-1b) for intra-peritoneal administration in recurrent ovarian cancer. J Transl Med 16:196. Scholar
  224. 224.
    de Gramont A, Gangji D, Louvet C et al (2002) Adoptive immunotherapy of ovarian carcinoma. Gynecol Oncol 86:102–103. Scholar
  225. 225.
    Thiounn N, Pages F, Mejean A et al (2002) Adoptive immunotherapy for superficial bladder cancer with autologous macrophage activated killer cells. J Urol 168:2373–2376. Scholar
  226. 226.
    Andreesen R, Scheibenbogen C, Brugger W et al (1990) Adoptive transfer of tumor cytotoxic macrophages generated in vitro from circulating blood monocytes: a new approach to cancer immunotherapy. Cancer Res 50:7450–7456PubMedGoogle Scholar
  227. 227.
    Thurner B, Haendle I, Röder C et al (2002) Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med 190:1669–1678. Scholar
  228. 228.
    Nestle FO, Alijagic S, Gilliet M et al (1998) Vaccination of melanoma patients with peptide- or tumor lysate pulsed dendritic cells. Nat Med 4:328. Scholar
  229. 229.
    Oshita C, Takikawa M, Kume A et al (2012) Dendritic cell-based vaccination in metastatic melanoma patients: phase II clinical trial. Oncol Rep 28:1131–1138. Scholar
  230. 230.
    Kimura Y, Tsukada J, Tomoda T et al (2011) Clinical and immunologic evaluation of dendritic cell-based immunotherapy in combination with gemcitabine and/or s-1 in patients with advanced pancreatic carcinoma. Pancreas 41:195–205. Scholar
  231. 231.
    Gun SY, Lee SWL, Sieow JL, Wong SC (2019) Targeting immune cells for cancer therapy. Redox Biol 25:101174. Scholar
  232. 232.
    Zang X, Zhao X, Hu H et al (2017) Nanoparticles for tumor immunotherapy. Eur J Pharm Biopharm 115:243–256. Scholar
  233. 233.
    Shen S, Zhang Y, Chen KG et al (2018) Cationic polymeric nanoparticle delivering CCR2 siRNA to inflammatory monocytes for tumor microenvironment modification and cancer therapy. Mol Pharm 15:3642–3653. Scholar
  234. 234.
    Zhang Y, Wu L, Li Z et al (2018) Glycocalyx-mimicking nanoparticles improve anti-PD-L1 cancer immunotherapy through reversion of tumor-associated macrophages. Biomacromolecules 19:2098–2108. Scholar
  235. 235.
    Dolina JS, Sung SSJ, Novobrantseva TI et al (2013) Lipidoid nanoparticles containing PD-L1 siRNA delivered in vivo enter Kupffer cells and enhance NK and CD8+ T cell-mediated hepatic antiviral immunity. Mol Ther Nucleic Acids 2:e72. Scholar
  236. 236.
    Hobo W, Novobrantseva TI, Fredrix H et al (2013) Improving dendritic cell vaccine immunogenicity by silencing PD-1 ligands using siRNA-lipid nanoparticles combined with antigen mRNA electroporation. Cancer Immunol Immunother 62:285–297. Scholar
  237. 237.
    Choi MR, Stanton-maxey KJ, Stanley JK et al (2007) A cellular Trojan Horse for delivery of therapeutic nanoparticles into tumors. Nano Lett 7:3759–3765. Scholar
  238. 238.
    Choi MR, Bardhan R, Stanton-Maxey KJ et al (2012) Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse. Cancer Nanotechnol 3:47–54. Scholar
  239. 239.
    Anselmo AC, Gilbert JB, Kumar S et al (2015) Monocyte-mediated delivery of polymeric backpacks to inflamed tissues: a generalized strategy to deliver drugs to treat inflammation. J Control Release 199:29–36. Scholar
  240. 240.
    Doshi N, Swiston AJ, Gilbert JB et al (2011) Cell-based drug delivery devices using phagocytosis-resistant backpacks. Adv Healthc Mater 23:105–109. Scholar
  241. 241.
    He X, Cao H, Wang H et al (2017) Inflammatory monocytes loading protease-sensitive nanoparticles enable lung metastasis targeting and intelligent drug release for anti-metastasis therapy. Nano Lett 17:5546–5554. Scholar
  242. 242.
    Busse A, Letsch A, Fusi A et al (2013) Characterization of small spheres derived from various solid tumor cell lines: are they suitable targets for T cells? Clin Exp Metastasis 30:781–791. Scholar
  243. 243.
    Shin Y, Han S, Jeon JS et al (2012) Microfluidic assay for simultaneous culture of multiple cell types on surfaces or within hydrogels. Proc Natl Acad Sci U S A 7:1247–1259. Scholar
  244. 244.
    Polacheck WJ, Zervantonakis IK, Kamm RD (2013) Tumor cell migration in complex microenvironments. Cell Mol Life Sci 70:1335–1356. Scholar
  245. 245.
    Baker BM, Chen CS (2012) Deconstructing the third dimension: how 3D culture microenvironments alter cellular cues. J Cell Sci 125:3015–3024. Scholar
  246. 246.
    Bissell M, Rizki A, Mian IS (2003) Tissue architecture: the ultimate regulator of breast epithelial function. Curr Opin Cell Biol 15:753–762. Scholar
  247. 247.
    Hickman JA, Graeser R, de Hoogt R et al (2014) Three-dimensional models of cancer for pharmacology and cancer cell biology: capturing tumor complexity in vitro/ex vivo. Biotechnol J 9:1115–1128. Scholar
  248. 248.
    Pampaloni F, Reynard EG, Stelzer EHK (2007) The third dimension bridges the gap between cell culture and live tissue. Nat Rev Mol Cell Biol 8:839. Scholar
  249. 249.
    Yamaguchi H, Wyckoff J, Condeelis J (2005) Cell migration in tumors. Curr Opin Cell Biol 17:559–564. Scholar
  250. 250.
    Roussos ET, Condeelis JS, Patsialou A (2011) Chemotaxis in cancer. Nat Rev Cancer 11:573–587. Scholar
  251. 251.
    Cheon DJ, Orsulic S (2011) Mouse models of cancer. Annu Rev Pathol Mech Dis 6:95–119. Scholar
  252. 252.
    Kimlin LC, Casagrande G, Virador VM (2013) In vitro three-dimensional (3D) models in cancer research: an update. Mol Carcinog 52:167–182. Scholar
  253. 253.
    Herschkowitz JI, Simin K, Weigman VJ et al (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8:R76. Scholar
  254. 254.
    Larue L, Beermann F (2007) Cutaneous melanoma in genetically modified animals. Pigment Cell Res 20:485–497. Scholar
  255. 255.
    Ledford H (2011) Translational research: 4 ways to fix the clinical trial. Nature 477:526–528. Scholar
  256. 256.
    Kapałczyńska M, Kolenda T, Przybyła W et al (2018) 2D and 3D cell cultures—a comparison of different types of cancer cell cultures. Arch Med Sci 14:910–919. Scholar
  257. 257.
    Sharma SV, Haber DA, Settleman J (2010) Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents. Nat Rev Cancer 10:241–253. Scholar
  258. 258.
    Lovitt CJ, Shelper TB, Avery VM (2016) Cancer drug discovery: recent innovative approaches to tumor modeling. Expert Opin Drug Discov 11:885–894. Scholar
  259. 259.
    Weiswald LB, Bellet D, Dangles-Marie V (2015) Spherical cancer models in tumor biology. Neoplasia 17:1–15. Scholar
  260. 260.
    Kuen J, Darowski D, Kluge T, Majety M (2017) Pancreatic cancer cell/fibroblast co-culture induces M2 like macrophages that influence therapeutic response in a 3D model. PLoS One 12:e0182039. Scholar
  261. 261.
    Linde N, Gutschalk CM, Hoffmann C et al (2012) Integrating macrophages into organotypic co-cultures: a 3D in vitro model to study tumor-associated macrophages. PLoS One 7:e40058. Scholar
  262. 262.
    Martinez-Marin D, Jarvis C, Nelius T et al (2017) PEDF increases the tumoricidal activity of macrophages towards prostate cancer cells in vitro. PLoS One 12:e0174968. Scholar
  263. 263.
    Rama-Esendagli D, Esendagli G, Yilmaz G, Guc D (2014) Spheroid formation and invasion capacity are differentially influenced by co-cultures of fibroblast and macrophage cells in breast cancer. Mol Biol Rep 41:2885–2892. Scholar
  264. 264.
    Weaver VM, Lelièvre S, Lakins JN et al (2002) β4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. Cancer Cell 2:205–216. Scholar
  265. 265.
    Padrón JM, Peters GJ (2006) Cytotoxicity of sphingoid marine compound analogs in mono-and multilayered solid tumor cell cultures. Invest New Drugs 24:195–202. Scholar
  266. 266.
    Fischbach C, Chen R, Matsumoto T et al (2007) Engineering tumors with 3D scaffolds. Nat Methods 4:855–860. Scholar
  267. 267.
    Smalley KSM, Haass NK, Brafford PA et al (2006) Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Mol Cancer Ther 5:1136–1180. Scholar
  268. 268.
    Feder-Mengus C, Ghosh S, Reschner A et al (2008) New dimensions in tumor immunology: what does 3D culture reveal? Trends Mol Med 14:333–340. Scholar
  269. 269.
    Meyer AS, Hughes-Alford SK, Kay JE et al (2012) 2D protrusion but not motility predicts growth factor-induced cancer cell migration in 3D collagen. J Cell Biol 197:721–729. Scholar
  270. 270.
    Fraley SI, Feng Y, Krishnamurthy R et al (2010) A distinctive role for focal adhesion proteins in three-dimensional cell motility. Nat Cell Biol 12:598–604. Scholar
  271. 271.
    Frick C, Dettinger P, Renkawitz J et al (2018) Nano-scale microfluidics to study 3D chemotaxis at the single cell level. PLoS One 13:e0198330. Scholar
  272. 272.
    Petersen OW, Ronnov-Jessen L, Howlett AR, Bissell MJ (2006) Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. Proc Natl Acad Sci U S A 89:9064–9068. Scholar
  273. 273.
    Boussommier-Calleja A, Li R, Chen MB et al (2016) Microfluidics: a new tool for modeling cancer-immune interactions. Trends in cancer 2:6–19. Scholar
  274. 274.
    Pavesi A, Tan AT, Koh S et al (2017) A 3D microfluidic model for preclinical evaluation of TCR-engineered T cells against solid tumors. J Clin Investig Insights 2:e89762. Scholar
  275. 275.
    Boussommier-Calleja A, Atiyas Y, Haase K et al (2019) The effects of monocytes on tumor cell extravasation in a 3D vascularized microfluidic model. Biomaterials 198:180–193. Scholar
  276. 276.
    Zervantonakis IK, Hughes-Alford SK, Charest JL et al (2012) Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function. Proc Natl Acad Sci U S A 109:13515–13520. Scholar
  277. 277.
    Li R, Serrano JC, Lee TA et al (2018) Interstitial flow promotes macrophage polarization toward an M2 phenotype. Mol Biol Cell 29:1927–1940. Scholar
  278. 278.
    Polacheck WJ, Charest JL, Kamm RD (2011) Interstitial flow influences direction of tumor cell migration through competing mechanisms. Proc Natl Acad Sci U S A 108:11115–11120. Scholar
  279. 279.
    Chang MY, Chan CK, Braun KR et al (2012) Monocyte-to-macrophage differentiation: synthesis and secretion of a complex extracellular matrix. J Biol Chem 287:14122–14135. Scholar
  280. 280.
    Adriani G, Pavesi A, Tan AT et al (2016) Microfluidic models for adoptive cell-mediated cancer immunotherapies. Drug Discov Today 21:1472–1478. Scholar
  281. 281.
    Chen MB, Hajal C, Benjamin DC et al (2018) Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation. Proc Natl Acad Sci U S A 115:7022–7027. Scholar
  282. 282.
    Spiegel A, Brooks MW, Houshyar S et al (2016) Neutrophils suppress intraluminal NK cell-mediated tumor cell clearance and enhance extravasation of disseminated carcinoma cells. Cancer Discov 6:630–649. Scholar
  283. 283.
    Agliari E, Biselli E, De Ninno A et al (2014) Cancer-driven dynamics of immune cells in a microfluidic environment. Sci Rep 4:6639. Scholar
  284. 284.
    Otano I, Escors D, Schurich A et al (2018) Molecular recalibration of PD-1+ antigen-specific T cells from blood and liver. Mol Ther 26:2553–2566. Scholar
  285. 285.
    Huang CP, Lu J, Seon H et al (2009) Engineering microscale cellular niches for three-dimensional multicellular co-cultures. Lab Chip 9:1740–1748. Scholar
  286. 286.
    Jenkins RW, Aref AR, Lizotte PH et al (2018) Ex vivo profiling of PD-1 blockade using organotypic tumor spheroids. Cancer Discov 8:196–215. Scholar
  287. 287.
    Liu PF, Cao YW, Zhang SD et al (2015) A bladder cancer microenvironment simulation system based on a microfluidic co-culture model. Oncotarget 6:37695–37705. Scholar
  288. 288.
    Aref AR, Campisi M, Ivanova E et al (2018) 3D microfluidic ex vivo culture of organotypic tumor spheroids to model immune checkpoint blockade. Lab Chip 18:3129–3143. Scholar
  289. 289.
    Parlato S, De Ninno A, Molfetta R et al (2017) 3D microfluidic model for evaluating immunotherapy efficacy by tracking dendritic cell behaviour toward tumor cells. Sci Rep 7:1093. Scholar
  290. 290.
    Moura Rosa P, Gopalakrishnan N, Ibrahim H et al (2016) The intercell dynamics of T cells and dendritic cells in a lymph node-on-a-chip flow device. Lab Chip 16:3728–3740. Scholar
  291. 291.
    Haessler U, Pisano M, Wu M, Swartz MA (2011) Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19. Proc Natl Acad Sci U S A 108:5614–5619. Scholar
  292. 292.
    Chen H, Shen H, Heimfeld S et al (2008) A microfluidic study of mouse dendritic cell membrane transport properties of water and cryoprotectants. Int J Heat Mass Transf 51:5687–5694. Scholar
  293. 293.
    Kiss M, Van Gassen S, Movahedi K et al (2018) Myeloid cell heterogeneity in cancer: not a single cell alike. Cell Immunol 330:188–201. Scholar
  294. 294.
    Campisi M, Shin Y, Osaki T et al (2018) 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes. Biomaterials 180:117–129. Scholar
  295. 295.
    Wang Y, Cuzzucoli F, Escobar A et al (2018) Tumor-on-a-chip platforms for assessing nanoparticle-based cancer therapy. Nanotechnology 29:332001. Scholar
  296. 296.
    Shang M, Soon RH, Lim CT et al (2019) Microfluidic modelling of the tumor microenvironment for anti-cancer drug development. Lab Chip 19:369. Scholar
  297. 297.
    Ronaldson-Bouchard K, Vunjak-Novakovic G (2018) Organs-on-a-chip: a fast track for engineered human tissues in drug development. Cell Stem Cell 22:310–324. Scholar
  298. 298.
    Adriani G, Bai J, Wong S et al (2016) M2a macrophages induce contact-dependent dispersion of carcinoma cell aggregates. Macrophage 3:e1222. Scholar
  299. 299.
    Hsu TH, Kao YL, Lin WL et al (2012) The migration speed of cancer cells influenced by macrophages and myofibroblasts co-cultured in a microfluidic chip. Integr Biol 4:177–182. Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Singapore-MIT Alliance for Research and Technology (SMART)BioSystems and Micromechanics (BioSyM) IRGSingaporeSingapore
  2. 2.Department of Microbiology and Immunology, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
  3. 3.Singapore Immunology Network (SIgN)Agency for Science, Technology and Research (A∗STAR)SingaporeSingapore
  4. 4.Department of Mechanical EngineeringMassachusetts Institute of TechnologyCambridgeUSA
  5. 5.Department of Biological EngineeringMassachusetts Institute of TechnologyCambridgeUSA
  6. 6.Department of MedicineUniversity of CalgaryCalgaryCanada

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