Advertisement

Cellular and Molecular Life Sciences

, Volume 73, Issue 13, pp 2411–2424 | Cite as

Tumor-associated macrophages and anti-tumor therapies: complex links

  • Cristina BelgiovineEmail author
  • Maurizio D’Incalci
  • Paola Allavena
  • Roberta Frapolli
Review

Abstract

Myeloid cells infiltrating the tumor microenvironment, especially tumor-associated macrophages (TAMs), are essential providers of cancer-related inflammation, a condition known to accelerate tumor progression and limit the response to anti-tumor therapies. As a matter of fact, TAMs may have a dual role while interfering with cancer treatments, as they can either promote or impair their functionality. Here we review the connection between macrophages and anticancer therapies; moreover, we provide an overview of the different strategies to target or re-program TAMs for therapeutic purposes.

Keywords

Cancer-related inflammation Tumor-associated macrophages Anti-tumor therapies Macrophage targeting Nanoparticles 

Abbreviations

TAMs

Tumor-associated macrophages

MPS

Mononuclear phagocyte system

EGF

Epidermal growth factor

FGF

Fibroblast growth factor

PlGF

Placental growth factor

Bv8

Prokineticin

ICD

Immunogenic cell death

DAMPs

Damage-associated molecular patterns

MDSC

Myeloid-derived suppressor cells

CSC

Cancer stem cells

MFG-E8

Milk fat globule epidermal growth factor-8

GIST

Gastrointestinal stroma tumors

ABL1

V-abl Abelson murine leukemia

TEM

Tie2-expressing monocytes

IGF1

Insulin growth factor 1

HER-2

Epidermal growth factor receptor-2

ADCC/ADCP

Antibody-dependent cellular cytotoxicity/phagocytosis

GM-CSF

Granulocyte–macrophage colony stimulating factor

CTLA-4

Cytotoxic T lymphocyte-associated protein 4

PD1

Programmed death protein 1

HCC

Hepatocellular carcinoma

CA-4-P

Combrestatin-A4-phosphate

ANG2

Angiopoietin 2

RECIST

Response evaluation criteria in solid tumors

NPs

Nanoparticle system

EPR

Enhanced permeability and retention

MC-TG

Polymeric micelles loaded with 6 thioguanine

OVA

Ovalbumin

CDP-NPS

Cyclodextrin-based polymer nanoparticles

MIF

Migration inhibitory factor

NO

Nitric oxide

PTHrP

Parathyroid hormone-related protein

References

  1. 1.
    Hume DA (2006) The mononuclear phagocyte system. Curr Opin Immunol 18(1):49–53. doi: 10.1189/jlb.0902450 PubMedCrossRefGoogle Scholar
  2. 2.
    Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496(7446):445–455. doi: 10.1038/nature12034 PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Martinez-Pomares L, Reid DM, Brown GD et al (2003) Analysis of mannose receptor regulation by IL-4, IL-10, and proteolytic processing using novel monoclonal antibodies. J Leukoc Biol 73(5):604–613. doi: 10.1189/jlb.0902450 PubMedCrossRefGoogle Scholar
  4. 4.
    Mantovani A, Sica A, Locati M (2005) Macrophage polarization comes of age. Immunity 23(4):344–346. doi: 10.1016/j.immuni.2005.10.001 PubMedCrossRefGoogle Scholar
  5. 5.
    Mantovani A, Sica A, Sozzani S et al (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25(12):677–686. doi: 10.1016/j.it.2004.09.015 PubMedCrossRefGoogle Scholar
  6. 6.
    Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136(7):2348–2357PubMedGoogle Scholar
  7. 7.
    Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5(12):953–964. doi: 10.1038/nri1733 PubMedCrossRefGoogle Scholar
  8. 8.
    Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555. doi: 10.1016/S1471-4906(02)02302-5 PubMedCrossRefGoogle Scholar
  9. 9.
    Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3(2):133–146. doi: 10.1038/nri1001 PubMedCrossRefGoogle Scholar
  10. 10.
    Murray PJ, Allen JE, Biswas SK et al (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41(1):14–20. doi: 10.1016/j.immuni.2014.06.008 PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Boorsma CE, Draijer C, Melgert BN (2013) Macrophage heterogeneity in respiratory diseases. Mediators Inflamm 2013:769214. doi: 10.1155/2013/769214 PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Chow A, Brown BD, Merad M (2011) Studying the mononuclear phagocyte system in the molecular age. Nat Rev Immunol 11(11):788–798. doi: 10.1038/nri3087 PubMedCrossRefGoogle Scholar
  13. 13.
    Edin S, Wikberg ML, Dahlin AM et al (2012) The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS One 7(10):e47045. doi: 10.1371/journal.pone.0047045 PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Hodge S, Matthews G, Mukaro V et al (2011) Cigarette smoke-induced changes to alveolar macrophage phenotype and function are improved by treatment with procysteine. Am J Respir Cell Mol Biol 44(5):673–681. doi: 10.1165/rcmb.2009-0459OC PubMedCrossRefGoogle Scholar
  15. 15.
    Lawrence T, Natoli G (2011) Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol 11(11):750–761. doi: 10.1038/nri3088 PubMedCrossRefGoogle Scholar
  16. 16.
    Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11(11):723–737. doi: 10.1038/nri3073 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Reinartz S, Schumann T, Finkernagel F et al (2014) Mixed-polarization phenotype of ascites-associated macrophages in human ovarian carcinoma: correlation of CD163 expression, cytokine levels and early relapse. Int J Cancer 134(1):32–42. doi: 10.1002/ijc.28335 PubMedCrossRefGoogle Scholar
  18. 18.
    Xue J, Schmidt SV, Sander J et al (2014) Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40(2):274–288. doi: 10.1016/j.immuni.2014.01.006 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Meissner F, Scheltema RA, Mollenkopf HJ, Mann M (2013) Direct proteomic quantification of the secretome of activated immune cells. Science 340(6131):475–478. doi: 10.1126/science.1232578 PubMedCrossRefGoogle Scholar
  20. 20.
    Coussens LM, Zitvogel L, Palucka AK (2013) Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 339(6117):286–291. doi: 10.1126/science.1232227 PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    DeNardo DG, Brennan DJ, Rexhepaj E et al (2011) Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1(1):54–67. doi: 10.1158/2159-8274.CD-10-0028 PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi: 10.1016/j.cell.2011.02.013 PubMedCrossRefGoogle Scholar
  23. 23.
    Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454(7203):436–444. doi: 10.1038/nature07205 PubMedCrossRefGoogle Scholar
  24. 24.
    Mantovani A, Bottazzi B, Colotta F, Sozzani S, Ruco L (1992) The origin and function of tumor-associated macrophages. Immunol Today 13(7):265–270. doi: 10.1016/0167-5699(92)90008-U PubMedCrossRefGoogle Scholar
  25. 25.
    Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122(3):787–795. doi: 10.1172/JCI59643 PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41(1):49–61. doi: 10.1016/j.immuni.2014.06.010 PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Jenkins SJ, Ruckerl D, Cook PC et al (2011) Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332(6035):1284–1288. doi: 10.1126/science.1204351 PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Franklin RA, Liao W, Sarkar A et al (2014) The cellular and molecular origin of tumor-associated macrophages. Science 344(6186):921–925. doi: 10.1126/science.1252510 PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Shand FH, Ueha S, Otsuji M et al (2014) Tracking of intertissue migration reveals the origins of tumor-infiltrating monocytes. Proc Natl Acad Sci USA 111(21):7771–7776. doi: 10.1073/pnas.1402914111 PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Bottazzi B, Erba E, Nobili N et al (1990) A paracrine circuit in the regulation of the proliferation of macrophages infiltrating murine sarcomas. J Immunol 144(6):2409–2412PubMedGoogle Scholar
  31. 31.
    Tymoszuk P, Evens H, Marzola V et al (2014) In situ proliferation contributes to accumulation of tumor-associated macrophages in spontaneous mammary tumors. Eur J Immunol 44(8):2247–2262. doi: 10.1002/eji.201344304 PubMedCrossRefGoogle Scholar
  32. 32.
    Colegio OR, Chu NQ, Szabo AL et al (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513(7519):559–563. doi: 10.1038/nature13490 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Datar I, Qiu X, Ma HZ et al (2015) RKIP regulates CCL5 expression to inhibit breast cancer invasion and metastasis by controlling macrophage infiltration. Oncotarget 6(36):39050–39061. doi: 10.18632/oncotarget.5176 PubMedPubMedCentralGoogle Scholar
  34. 34.
    De Palma M, Lewis CE (2013) Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23(3):277–286. doi: 10.1016/j.ccr.2013.02.013 PubMedCrossRefGoogle Scholar
  35. 35.
    Frankenberger C, Rabe D, Bainer R et al (2015) Metastasis suppressors regulate the tumor microenvironment by blocking recruitment of prometastatic tumor-associated macrophages. Cancer Res 75(19):4063–4073. doi: 10.1158/0008-5472.CAN-14-3394 PubMedCrossRefGoogle Scholar
  36. 36.
    Ruffell B, Affara NI, Coussens LM (2012) Differential macrophage programming in the tumor microenvironment. Trends Immunol 33(3):119–126. doi: 10.1016/j.it.2011.12.001 PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Velasco-Velazquez M, Jiao X, De La Fuente M et al (2012) CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res 72(15):3839–3850. doi: 10.1158/0008-5472.CAN-11-3917 PubMedCrossRefGoogle Scholar
  38. 38.
    Weitzenfeld P, Ben-Baruch A (2014) The chemokine system, and its CCR5 and CXCR4 receptors, as potential targets for personalized therapy in cancer. Cancer Lett 352(1):36–53. doi: 10.1016/j.canlet.2013.10.006 PubMedCrossRefGoogle Scholar
  39. 39.
    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(11):1105–1117. doi: 10.1038/ncb3041 PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Su S, Liu Q, Chen J et al (2014) A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell 25(5):605–620. doi: 10.1016/j.ccr.2014.03.021 PubMedCrossRefGoogle Scholar
  41. 41.
    Bonavita E, Gentile S, Rubino M et al (2015) PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160(4):700–714. doi: 10.1016/j.cell.2015.01.004 PubMedCrossRefGoogle Scholar
  42. 42.
    Beck AH, Espinosa I, Edris B et al (2009) The macrophage colony-stimulating factor 1 response signature in breast carcinoma. Clin Cancer Res 15(3):778–787. doi: 10.1158/1078-0432.CCR-08-1283 PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Finak G, Bertos N, Pepin F et al (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14(5):518–527. doi: 10.1038/nm1764 PubMedCrossRefGoogle Scholar
  44. 44.
    Lenz G, Wright G, Dave SS et al (2008) Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 359(22):2313–2323.  doi: 10.1056/NEJMoa0802885 PubMedCrossRefGoogle Scholar
  45. 45.
    Balkwill F (2006) TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev 25(3):409–416. doi: 10.1007/s10555-006-9005-3 PubMedCrossRefGoogle Scholar
  46. 46.
    Barcellos-Hoff MH, Lyden D, Wang TC (2013) The evolution of the cancer niche during multistage carcinogenesis. Nat Rev Cancer 13(7):511–518. doi: 10.1038/nrc3536 PubMedCrossRefGoogle Scholar
  47. 47.
    Liu Y, Li PK, Li C, Lin J (2010) Inhibition of STAT3 signaling blocks the anti-apoptotic activity of IL-6 in human liver cancer cells. J Biol Chem 285(35):27429–27439. doi: 10.1074/jbc.M110.142752 PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Mantovani A, Savino B, Locati M et al (2010) The chemokine system in cancer biology and therapy. Cytokine Growth Factor Rev 21(1):27–39. doi: 10.1016/j.cytogfr.2009.11.007 PubMedCrossRefGoogle Scholar
  49. 49.
    Kim S, Takahashi H, Lin WW et al (2009) Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457(7225):102–106. doi: 10.1038/nature07623 PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Pignatelli J, Goswami S, Jones JG et al (2014) Invasive breast carcinoma cells from patients exhibit MenaINV- and macrophage-dependent transendothelial migration. Sci Signal 7(353):ra112. doi: 10.1126/scisignal.2005329 PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Sangaletti S, Tripodo C, Sandri S et al (2014) Osteopontin shapes immunosuppression in the metastatic niche. Cancer Res 74(17):4706–4719. doi: 10.1158/0008-5472.CAN-13-3334 PubMedCrossRefGoogle Scholar
  52. 52.
    Guo C, Buranych A, Sarkar D, Fisher PB, Wang XY (2013) The role of tumor-associated macrophages in tumor vascularization. Vasc Cell 5(1):20. doi: 10.1186/2045-824X-5-20 PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Lin EY, Li JF, Gnatovskiy L et al (2006) Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66(23):11238–11246. doi: 10.1158/0008-5472.CAN-06-1278 PubMedCrossRefGoogle Scholar
  54. 54.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. doi: 10.1038/nrc3239 PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Affara NI, Ruffell B, Medler TR et al (2014) B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell 25(6):809–821. doi: 10.1016/j.ccr.2014.04.026 PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    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(8):2480–2492. doi: 10.1158/0008-5472.CAN-12-3542 PubMedCrossRefGoogle Scholar
  57. 57.
    Mantovani A, Allavena P (2015) The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med 212(4):435–445. doi: 10.1084/jem.20150295 PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Paulus P, Stanley ER, Schafer R, Abraham D, Aharinejad S (2006) Colony-stimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts. Cancer Res 66(8):4349–4356. doi: 10.1158/0008-5472.CAN-05-3523 PubMedCrossRefGoogle Scholar
  59. 59.
    Shree T, Olson OC, Elie BT et al (2011) Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev 25(23):2465–2479. doi: 10.1101/gad.180331.111 PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Pyonteck SM, Akkari L, Schuhmacher AJ et al (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19(10):1264–1272. doi: 10.1038/nm.3337 PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    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(30):12425–12430. doi: 10.1073/pnas.1106645108 PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    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(3):1128–1141. doi: 10.1158/0008-5472.CAN-12-2731 PubMedCrossRefGoogle Scholar
  63. 63.
    Bruchard M, Mignot G, Derangere V et al (2013) Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat Med 19(1):57–64. doi: 10.1038/nm.2999 PubMedCrossRefGoogle Scholar
  64. 64.
    Nakasone ES, Askautrud HA, Kees T et al (2012) Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 21(4):488–503. doi: 10.1016/j.ccr.2012.02.017 PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Mantovani A, Polentarutti N, Luini W, Peri G, Spreafico F (1979) Role of host defense mechanisms in the antitumor activity of adriamycin and daunomycin in mice. J Natl Cancer Inst 63(1):61–66PubMedGoogle Scholar
  66. 66.
    Kroemer G, Galluzzi L, Kepp O, Zitvogel L (2013) Immunogenic cell death in cancer therapy. Annu Rev Immunol 31:51–72. doi: 10.1146/annurev-immunol-032712-100008 PubMedCrossRefGoogle Scholar
  67. 67.
    Bezu L, Gomes-de-Silva LC, Dewitte H et al (2015) Combinatorial strategies for the induction of immunogenic cell death. Front Immunol 6:187. doi: 10.3389/fimmu.2015.00187 PubMedPubMedCentralGoogle Scholar
  68. 68.
    Kodumudi KN, Woan K, Gilvary DL et al (2010) A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res 16(18):4583–4594. doi: 10.1158/1078-0432.CCR-10-0733 PubMedCrossRefGoogle Scholar
  69. 69.
    Medina-Echeverz J, Fioravanti J, Zabala M et al (2011) Successful colon cancer eradication after chemoimmunotherapy is associated with profound phenotypic change of intratumoral myeloid cells. J Immunol 186(2):807–815. doi: 10.4049/jimmunol.1001483 PubMedCrossRefGoogle Scholar
  70. 70.
    Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603. doi: 10.1038/nrc2442 PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Coffelt SB, Lewis CE, Naldini L et al (2010) Elusive identities and overlapping phenotypes of proangiogenic myeloid cells in tumors. Am J Pathol 176(4):1564–1576. doi: 10.2353/ajpath.2010.090786 PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Barleon B, Sozzani S, Zhou D et al (1996) Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87(8):3336–3343PubMedGoogle Scholar
  73. 73.
    Ferrara N (2010) Role of myeloid cells in vascular endothelial growth factor-independent tumor angiogenesis. Curr Opin Hematol 17(3):219–224. doi: 10.1097/MOH.0b013e3283386660 PubMedGoogle Scholar
  74. 74.
    Gabrusiewicz K, Liu D, Cortes-Santiago N et al (2014) Anti-vascular endothelial growth factor therapy-induced glioma invasion is associated with accumulation of Tie2-expressing monocytes. Oncotarget 5(8):2208–2220. doi: 10.18632/oncotarget.1893 PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Lu-Emerson C, Snuderl M, Kirkpatrick ND et al (2013) Increase in tumor-associated macrophages after antiangiogenic therapy is associated with poor survival among patients with recurrent glioblastoma. Neuro Oncol 15(8):1079–1087. doi: 10.1093/neuonc/not082 PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    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(4):512–526. doi: 10.1016/j.ccr.2011.02.005 PubMedCrossRefGoogle Scholar
  77. 77.
    Chung AS, Lee J, Ferrara N (2010) Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer 10(7):505–514. doi: 10.1038/nrc2868 PubMedCrossRefGoogle Scholar
  78. 78.
    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(13):3420–3430. doi: 10.1158/1078-0432.CCR-09-2904 PubMedCrossRefGoogle Scholar
  79. 79.
    Welford AF, Biziato D, Coffelt SB et al (2011) TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice. J Clin Invest 121(5):1969–1973. doi: 10.1172/JCI44562 PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Daly C, Eichten A, Castanaro C et al (2013) Angiopoietin-2 functions as a Tie2 agonist in tumor models, where it limits the effects of VEGF inhibition. Cancer Res 73(1):108–118. doi: 10.1158/0008-5472.CAN-12-2064 PubMedCrossRefGoogle Scholar
  81. 81.
    Srivastava K, Hu J, Korn C et al (2014) Postsurgical adjuvant tumor therapy by combining anti-angiopoietin-2 and metronomic chemotherapy limits metastatic growth. Cancer Cell 26(6):880–895. doi: 10.1016/j.ccell.2014.11.005 PubMedCrossRefGoogle Scholar
  82. 82.
    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(7):1461–1471. doi: 10.1182/blood-2009-08-237412 PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    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(3):272–281. doi: 10.1038/sj.bjc.6603240 PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Barcellos-Hoff MH, Park C, Wright EG (2005) Radiation and the microenvironment—tumorigenesis and therapy. Nat Rev Cancer 5(11):867–875. doi: 10.1038/nrc1735 PubMedCrossRefGoogle Scholar
  85. 85.
    Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M (2013) Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229(2):176–185. doi: 10.1002/path.4133 PubMedCrossRefGoogle Scholar
  86. 86.
    Milas L, Iwakawa M, Hunter N (1987) Enhancement of lung colony formation by admixing irradiated with viable tumor cells: dependence on host status. Clin Exp Metastasis 5(3):213–217PubMedCrossRefGoogle Scholar
  87. 87.
    Moding EJ, Kastan MB, Kirsch DG (2013) Strategies for optimizing the response of cancer and normal tissues to radiation. Nat Rev Drug Discov 12(7):526–542. doi: 10.1038/nrd4003 PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Moeller BJ, Dewhirst MW (2004) Raising the bar: how HIF-1 helps determine tumor radiosensitivity. Cell Cycle 3(9):1107–1110PubMedCrossRefGoogle Scholar
  89. 89.
    Russell JS, Brown JM (2013) The irradiated tumor microenvironment: role of tumor-associated macrophages in vascular recovery. Frontiers in physiology 4:157. doi: 10.3389/fphys.2013.00157 PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Shiao SL, Coussens LM (2010) The tumor-immune microenvironment and response to radiation therapy. J Mammary Gland Biol Neoplasia 15(4):411–421. doi: 10.1007/s10911-010-9194-9 PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Xu J, Escamilla J, Mok S et al (2013) CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res 73(9):2782–2794. doi: 10.1158/0008-5472.CAN-12-3981 PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Chen C, Shang X, Xu T et al (2007) c-Abl is required for the signaling transduction induced by L-selectin ligation. Eur J Immunol 37(11):3246–3258. doi: 10.1002/eji.200737221 PubMedCrossRefGoogle Scholar
  93. 93.
    Ahn GO, Tseng D, Liao CH et al (2010) Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proc Natl Acad Sci USA 107(18):8363–8368. doi: 10.1073/pnas.0911378107 PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    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(3):694–705. doi: 10.1172/JCI40283 PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Weigert A, Brune B (2008) Nitric oxide, apoptosis and macrophage polarization during tumor progression. Nitric Oxide Biol Chem Off J Nitric Oxide Soc 19(2):95–102. doi: 10.1016/j.niox.2008.04.021 CrossRefGoogle Scholar
  96. 96.
    Rahat MA, Hemmerlein B (2013) Macrophage-tumor cell interactions regulate the function of nitric oxide. Front Physiol 4:144. doi: 10.3389/fphys.2013.00144 PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Hussain SP, Hofseth LJ, Harris CC (2003) Radical causes of cancer. Nat Rev Cancer 3(4):276–285. doi: 10.1038/nrc1046 PubMedCrossRefGoogle Scholar
  98. 98.
    Ridnour LA, Windhausen AN, Isenberg JS et al (2007) Nitric oxide regulates matrix metalloproteinase-9 activity by guanylyl-cyclase-dependent and -independent pathways. Proc Natl Acad Sci USA 104(43):16898–16903. doi: 10.1073/pnas.0702761104 PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Ziche M, Morbidelli L (2009) Molecular regulation of tumour angiogenesis by nitric oxide. Eur Cytokine Netw 20(4):164–170. doi: 10.1684/ecn.2009.0169 PubMedGoogle Scholar
  100. 100.
    Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC (2013) An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res 1(6):365–372. doi: 10.1158/2326-6066.CIR-13-0115 PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Golden EB, Frances D, Pellicciotta I et al (2014) Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology 3:e28518. doi: 10.4161/onci.28518 PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Durante M, Reppingen N, Held KD (2013) Immunologically augmented cancer treatment using modern radiotherapy. Trends Mol Med 19(9):565–582. doi: 10.1016/j.molmed.2013.05.007 PubMedCrossRefGoogle Scholar
  103. 103.
    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(5):589–602. doi: 10.1016/j.ccr.2013.09.014 PubMedCrossRefGoogle Scholar
  104. 104.
    Furness AJ, Vargas FA, Peggs KS, Quezada SA (2014) Impact of tumour microenvironment and Fc receptors on the activity of immunomodulatory antibodies. Trends Immunol 35(7):290–298. doi: 10.1016/j.it.2014.05.002 PubMedCrossRefGoogle Scholar
  105. 105.
    Sliwkowski MX, Mellman I (2013) Antibody therapeutics in cancer. Science 341(6151):1192–1198. doi: 10.1126/science.1241145 PubMedCrossRefGoogle Scholar
  106. 106.
    Park S, Jiang Z, Mortenson ED et al (2010) The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell 18(2):160–170. doi: 10.1016/j.ccr.2010.06.014 PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Uchida J, Hamaguchi Y, Oliver JA et al (2004) The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med 199(12):1659–1669. doi: 10.1084/jem.20040119 PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    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(5):699–713. doi: 10.1016/j.cell.2010.07.044 PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Tamura K, Shimizu C, Hojo T et al (2011) FcgammaR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer. Ann Oncol 22(6):1302–1307. doi: 10.1093/annonc/mdq585 PubMedCrossRefGoogle Scholar
  110. 110.
    Weng WK, Levy R (2003) Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol Off J Am Soc Clin Oncol 21(21):3940–3947. doi: 10.1200/JCO.2003.05.013 CrossRefGoogle Scholar
  111. 111.
    Zhang W, Gordon M, Schultheis AM et al (2007) FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol Off J Am Soc Clin Oncol 25(24):3712–3718. doi: 10.1200/JCO.2006.08.8021 CrossRefGoogle Scholar
  112. 112.
    Cartron G, Zhao-Yang L, Baudard M et al (2008) Granulocyte-macrophage colony-stimulating factor potentiates rituximab in patients with relapsed follicular lymphoma: results of a phase II study. J Clin Oncol 26:2725–2731. doi: 10.1200/JCO.2007.13.7729 PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Cheung NK, Cheung IY, Kramer K et al (2014) Key role for myeloid cells: phase II results of anti-G(D2) antibody 3F8 plus granulocyte-macrophage colony-stimulating factor for chemoresistant osteomedullary neuroblastoma. Int J Cancer 135(9):2199–2205. doi: 10.1002/ijc.28851 PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Galluzzi L, Vacchelli E, Bravo-San Pedro JM et al (2014) Classification of current anticancer immunotherapies. Oncotarget 5(24):12472–12508. doi: 10.18632/oncotarget.2998 PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Weiskopf K, Weissman IL (2015) Macrophages are critical effectors of antibody therapies for cancer. MAbs 7(2):303–310. doi: 10.1080/19420862.2015.1011450 PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Selby MJ, Engelhardt JJ, Quigley M et al (2013) Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res 1(1):32–42. doi: 10.1158/2326-6066.CIR-13-0013 PubMedCrossRefGoogle Scholar
  117. 117.
    Simpson TR, Li F, Montalvo-Ortiz W et al (2013) Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 210(9):1695–1710. doi: 10.1084/jem.20130579 PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Mizutani K, Sud S, McGregor NA et al (2009) The chemokine CCL2 increases prostate tumor growth and bone metastasis through macrophage and osteoclast recruitment. Neoplasia 11(11):1235–1242. doi: 10.1593/neo.09988 PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Gazzaniga S, Bravo AI, Guglielmotti A et al (2007) Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft. J Invest Dermatol 127(8):2031–2041. doi: 10.1038/sj.jid.5700827 PubMedCrossRefGoogle Scholar
  120. 120.
    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(19):9417–9424. doi: 10.1158/0008-5472.CAN-07-1286 PubMedCrossRefGoogle Scholar
  121. 121.
    Lu X, Kang Y (2009) Chemokine (C-C motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone. J Biol Chem 284(42):29087–29096. doi: 10.1074/jbc.M109.035899 PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Moisan F, Francisco EB, Brozovic A et al (2014) Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers. Mol Oncol 8(7):1231–1239. doi: 10.1016/j.molonc.2014.03.016 PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Zollo M, Di Dato V, Spano D et al (2012) Targeting monocyte chemotactic protein-1 synthesis with bindarit induces tumor regression in prostate and breast cancer animal models. Clin Exp Metastasis 29(6):585–601. doi: 10.1007/s10585-012-9473-5 PubMedCrossRefGoogle Scholar
  124. 124.
    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(4):1041–1050. doi: 10.1007/s00280-013-2099-8 PubMedCrossRefGoogle Scholar
  125. 125.
    Pienta KJ, Machiels JP, Schrijvers D et al (2013) Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer. Invest New Drugs 31(3):760–768. doi: 10.1007/s10637-012-9869-8 PubMedCrossRefGoogle Scholar
  126. 126.
    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(1):111–123. doi: 10.1007/s11523-014-0320-2 PubMedCrossRefGoogle Scholar
  127. 127.
    Hume DA, MacDonald KP (2012) Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood 119(8):1810–1820. doi: 10.1182/blood-2011-09-379214 PubMedCrossRefGoogle Scholar
  128. 128.
    Aharinejad S, Salama M, Paulus P et al (2013) Elevated CSF1 serum concentration predicts poor overall survival in women with early breast cancer. Endocr Relat Cancer 20(6):777–783. doi: 10.1530/ERC-13-0198 PubMedCrossRefGoogle Scholar
  129. 129.
    Jia JB, Wang WQ, Sun HC et al (2010) High expression of macrophage colony-stimulating factor-1 receptor in peritumoral liver tissue is associated with poor outcome in hepatocellular carcinoma after curative resection. Oncologist 15(7):732–743. doi: 10.1634/theoncologist.2009-0170 PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Koh YW, Park C, Yoon DH, Suh C, Huh J (2014) CSF-1R expression in tumor-associated macrophages is associated with worse prognosis in classical Hodgkin lymphoma. Am J Clin Pathol 141(4):573–583. doi: 10.1309/AJCPR92TDDFARISU PubMedCrossRefGoogle Scholar
  131. 131.
    Zhu XD, Zhang JB, Zhuang PY et al (2008) High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol 26(16):2707–2716. doi: 10.1200/JCO.2007.15.6521 PubMedCrossRefGoogle Scholar
  132. 132.
    Lin EY, Nguyen AV, Russell RG, Pollard JW (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193(6):727–740. doi: 10.1084/jem.193.6.727 PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Pyonteck SM, Gadea BB, Wang HW et al (2012) Deficiency of the macrophage growth factor CSF-1 disrupts pancreatic neuroendocrine tumor development. Oncogene 31(11):1459–1467. doi: 10.1038/onc.2011.337 PubMedCrossRefGoogle Scholar
  134. 134.
    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(6):846–859. doi: 10.1016/j.ccr.2014.05.016 PubMedCrossRefGoogle Scholar
  135. 135.
    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(1):153–161. doi: 10.1158/0008-5472.CAN-13-1816 PubMedCrossRefGoogle Scholar
  136. 136.
    Weizman N, Krelin Y, Shabtay-Orbach A et al (2014) Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. Oncogene 33(29):3812–3819. doi: 10.1038/onc.2013.357 PubMedCrossRefGoogle Scholar
  137. 137.
    Luckman SP, Hughes DE, Coxon FP et al (1998) Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 13(4):581–589. doi: 10.1359/jbmr.1998.13.4.581 PubMedCrossRefGoogle Scholar
  138. 138.
    Russell RG, Rogers MJ (1999) Bisphosphonates: from the laboratory to the clinic and back again. Bone 25(1):97–106PubMedCrossRefGoogle Scholar
  139. 139.
    Mundy GR (2002) Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2(8):584–593. doi: 10.1038/nrc867 PubMedCrossRefGoogle Scholar
  140. 140.
    Cecchini MG, Fleisch H (1990) Bisphosphonates in vitro specifically inhibit, among the hematopoietic series, the development of the mouse mononuclear phagocyte lineage. J Bone Miner Res 5(10):1019–1027. doi: 10.1002/jbmr.5650051005 PubMedCrossRefGoogle Scholar
  141. 141.
    Dunford JE, Thompson K, Coxon FP et al (2001) Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 296(2):235–242PubMedGoogle Scholar
  142. 142.
    Monkkonen H, Auriola S, Lehenkari P et al (2006) A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates. Br J Pharmacol 147(4):437–445. doi: 10.1038/sj.bjp.0706628 PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Moreau MF, Guillet C, Massin P et al (2007) Comparative effects of five bisphosphonates on apoptosis of macrophage cells in vitro. Biochem Pharmacol 73(5):718–723. doi: 10.1016/j.bcp.2006.09.031 PubMedCrossRefGoogle Scholar
  144. 144.
    Rogers MJ, Chilton KM, Coxon FP et al (1996) Bisphosphonates induce apoptosis in mouse macrophage-like cells in vitro by a nitric oxide-independent mechanism. J Bone Miner Res 11(10):1482–1491. doi: 10.1002/jbmr.5650111015 PubMedCrossRefGoogle Scholar
  145. 145.
    Rogers MJ, Gordon S, Benford HL et al (2000) Cellular and molecular mechanisms of action of bisphosphonates. Cancer 88(12 Suppl):2961–2978. doi: 10.1002/1097-0142(20000615)88:12+<2961:AID-CNCR12>3.0.CO;2-L PubMedCrossRefGoogle Scholar
  146. 146.
    Van Rooijen N, Sanders A (1994) Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Methods 174(1–2):83–93PubMedCrossRefGoogle Scholar
  147. 147.
    Miselis NR, Wu ZJ, Van Rooijen N, Kane AB (2008) Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma. Mol Cancer Ther 7(4):788–799. doi: 10.1158/1535-7163.MCT-07-0579 PubMedCrossRefGoogle Scholar
  148. 148.
    Fritz JM, Tennis MA, Orlicky DJ et al (2014) Depletion of tumor-associated macrophages slows the growth of chemically induced mouse lung adenocarcinomas. Front Immunol 5:587. doi: 10.3389/fimmu.2014.00587 PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    D’Incalci M, Galmarini CM (2010) A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther 9(8):2157–2163. doi: 10.1158/1535-7163.MCT-10-0263 PubMedCrossRefGoogle Scholar
  150. 150.
    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(4):646–650. doi: 10.1038/bjc.2014.149 PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Allavena P, Signorelli M, Chieppa M et al (2005) Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production. Cancer Res 65(7):2964–2971. doi: 10.1158/0008-5472.CAN-04-4037 PubMedCrossRefGoogle Scholar
  152. 152.
    Germano G, Frapolli R, Simone M et al (2010) Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res 70(6):2235–2244. doi: 10.1158/0008-5472.CAN-09-2335 PubMedCrossRefGoogle Scholar
  153. 153.
    Germano G, Frapolli R, Belgiovine C et al (2013) Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 23(2):249–262. doi: 10.1016/j.ccr.2013.01.008 PubMedCrossRefGoogle Scholar
  154. 154.
    Luo Y, Knudson MJ (2010) Mycobacterium bovis bacillus Calmette-Guerin-induced macrophage cytotoxicity against bladder cancer cells. Clin Dev Immunol 2010:357591. doi: 10.1155/2010/357591 PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Prada CE, Jousma E, Rizvi TA et al (2013) Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol 125(1):159–168. doi: 10.1007/s00401-012-1056-7 PubMedCrossRefGoogle Scholar
  156. 156.
    Wang B, Li Q, Qin L et al (2011) Transition of tumor-associated macrophages from MHC class II(hi) to MHC class II(low) mediates tumor progression in mice. BMC Immunol 12:43. doi: 10.1186/1471-2172-12-43 PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Corthay A, Skovseth DK, Lundin KU et al (2005) Primary antitumor immune response mediated by CD4+ T cells. Immunity 22(3):371–383. doi: 10.1016/j.immuni.2005.02.003 PubMedCrossRefGoogle Scholar
  158. 158.
    Hagemann T, Lawrence T, McNeish I et al (2008) “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med 205(6):1261–1268. doi: 10.1084/jem.20080108 PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Jaiswal S, Chao MP, Majeti R, Weissman IL (2010) Macrophages as mediators of tumor immunosurveillance. Trends Immunol 31(6):212–219. doi: 10.1016/j.it.2010.04.001 PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Beatty GL, Torigian DA, Chiorean EG et al (2013) A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res 19(22):6286–6295. doi: 10.1158/1078-0432.CCR-13-1320 PubMedCrossRefGoogle Scholar
  161. 161.
    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(6):695–709. doi: 10.1016/j.ccr.2013.11.007 PubMedCrossRefGoogle Scholar
  162. 162.
    Laoui D, Van Overmeire E, Di Conza G et al (2014) Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res 74(1):24–30. doi: 10.1158/0008-5472.CAN-13-1196 PubMedCrossRefGoogle Scholar
  163. 163.
    Trotta F, Leufkens HG, Schellens JH, Laing R, Tafuri G (2011) Evaluation of oncology drugs at the European Medicines Agency and US Food and Drug Administration: when differences have an impact on clinical practice. J Clin Oncol Off J Am Soc Clin Oncol 29(16):2266–2272. doi: 10.1200/JCO.2010.34.1248 CrossRefGoogle Scholar
  164. 164.
    Jain RK, Stylianopoulos T (2010) Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 7(11):653–664. doi: 10.1038/nrclinonc.2010.139 PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Jeanbart L, Kourtis IC, van der Vlies AJ, Swartz MA, Hubbell JA (2015) 6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice. Cancer Immunol Immunother. doi: 10.1007/s00262-015-1702-8 PubMedPubMedCentralGoogle Scholar
  166. 166.
    Choi MR, Stanton-Maxey KJ, Stanley JK et al (2007) A cellular Trojan Horse for delivery of therapeutic nanoparticles into tumors. Nano Lett 7(12):3759–3765. doi: 10.1021/nl072209h PubMedCrossRefGoogle Scholar
  167. 167.
    Alizadeh D, Zhang L, Hwang J, Schluep T, Badie B (2010) Tumor-associated macrophages are predominant carriers of cyclodextrin-based nanoparticles into gliomas. Nanomedicine 6(2):382–390. doi: 10.1016/j.nano.2009.10.001 PubMedGoogle Scholar
  168. 168.
    Bumcrot D, Manoharan M, Koteliansky V, Sah DW (2006) RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat Chem Biol 2(12):711–719. doi: 10.1038/nchembio839 PubMedCrossRefGoogle Scholar
  169. 169.
    Deng Y, Wang CC, Choy KW et al (2014) Therapeutic potentials of gene silencing by RNA interference: principles, challenges, and new strategies. Gene 538(2):217–227. doi: 10.1016/j.gene.2013.12.019 PubMedCrossRefGoogle Scholar
  170. 170.
    Aagaard L, Rossi JJ (2007) RNAi therapeutics: principles, prospects and challenges. Adv Drug Deliv Rev 59(2–3):75–86. doi: 10.1016/j.addr.2007.03.005 PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Zhang M, Gao Y, Caja K, Zhao B, Kim JA (2015) Non-viral nanoparticle delivers small interfering RNA to macrophages in vitro and in vivo. PLoS One 10(3):e0118472. doi: 10.1371/journal.pone.0118472 PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Zhao X, Matlung H, Kuijpers TW, van den Berg TK (2013) On the mechanism and benefit of siRNA-mediated targeting of CD47 in cancer. Mol Ther 21(10):1811. doi: 10.1038/mt.2013.205 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  • Cristina Belgiovine
    • 1
    Email author
  • Maurizio D’Incalci
    • 2
  • Paola Allavena
    • 1
  • Roberta Frapolli
    • 2
  1. 1.Department Immunology and InflammationIRCCS Clinical and Research Institute HumanitasRozzanoItaly
  2. 2.Department of OncologyIRCCS Istituto di Ricerche Farmacologiche Mario NegriMilanItaly

Personalised recommendations