Innate Immune Cells in Breast Cancer – From Villains to Heroes?

  • Tim Kees
  • Mikala Egeblad


The innate immune system ensures effective protection against foreign pathogens and plays important roles in tissue remodeling. There are many types of innate immune cells, including monocytes, macrophages, dendritic cells, and granulocytes. Interestingly, these cells accumulate in most solid tumors, including those of the breast. There, they play a tumor-promoting role through secretion of growth and angiogenic factors, as well as immunosuppressive molecules. This is in strong contrast to the tumor-suppressing effects that innate immune cells exert in vitro upon proper activation. Therapeutic approaches have been developed with the aim of achieving similar suppressive activities in vivo. However, multiple factors in the tumor microenvironment, many of which are immunosuppressive, represent a major obstacle to effective treatment. Here, we discuss the potential of combating breast cancer through activation of the innate immune system, including possible strategies to enhance the success of immunotherapy.


Innate immune cells Immunotherapy Macrophages Tumor microenvironment Tumor-suppressing immune activities 

List of Abbreviations


Bacillus Calmette-Guerin


cluster of differentiation


colony stimulating factor-1


dendritic cell


epidermal growth factor


Fas ligand


fibroblast growth factor


granulocyte macrophage colony stimulating factor


human epidermal growth factor receptor 2


high mobility group box protein-1


heat shock protein






leukocyte-associated immunoglobulin-like receptor




myeloid derived suppressor cells


matrix metalloproteinase

NK cell

natural killer cell


nucleotide-binding oligomerization domain (NOD)-containing protein like receptor


nitric oxide


pathogen associated molecular pattern


programmed cell death receptor ligand


reactive oxygen species


spontaneous regression/complete resistance


signal transducer and activator of transcription


tumor associated macrophage


transforming growth factor-β


type I T helper cell


type II T helper cell


toll-like receptor


tumor necrosis factor-α


TNF-related apoptosis-inducing ligand


regulatory T cell


vascular endothelial growth factor


zoledronic acid



We thank Elizabeth Nakasone, Jae-Hyun Park, and Miriam Fein for help with the layout of the figures and comments on the manuscript.


  1. 1.
    Kopp E, Medzhitov R. Recognition of microbial infection by Toll-like receptors. Curr Opin Immunol. 2003;15:396–401.PubMedCrossRefGoogle Scholar
  2. 2.
    Mantovani A, Sica A, Locati M. Macrophage polarization comes of age. Immunity. 2005;23:344–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Weigert A, Jennewein C, Brune B. The liaison between apoptotic cells and macrophages–the end programs the beginning. Biol Chem. 2009;390:379–90.PubMedCrossRefGoogle Scholar
  4. 4.
    Gouon-Evans V, Lin EY, Pollard JW. Requirement of macrophages and eosinophils and their cytokines/chemokines for mammary gland development. Breast Cancer Res. 2002;4:155–64.PubMedCrossRefGoogle Scholar
  5. 5.
    Coussens LM, Pollard JW. Leukocytes in mammary development and cancer. Cold Spring Harb Perspect Biol. 2011;3:pii: a003285. doi: 10.1101/cshperspect.a003285.PubMedCrossRefGoogle Scholar
  6. 6.
    Atabai K, Sheppard D, Werb Z. Roles of the innate immune system in mammary gland remodeling during involution. J Mammary Gland Biol Neoplasia. 2007;12:37–45.PubMedCrossRefGoogle Scholar
  7. 7.
    Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817–26.PubMedCrossRefGoogle Scholar
  8. 8.
    Campbell MJ, Tonlaar NY, Garwood ER, Huo D, Moore DH, Khramtsov AI, et al. Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Res Treat 2010;Sep 15. [Epub ahead of print].Google Scholar
  9. 9.
    Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol. 2010;22:231–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66:605–12.PubMedCrossRefGoogle Scholar
  11. 11.
    Fidler IJ, Schroit AJ. Recognition and destruction of neoplastic cells by activated macrophages: discrimination of altered self. Biochim Biophys Acta. 1988;948:151–73.PubMedGoogle Scholar
  12. 12.
    Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev. 2003;8:223–46.PubMedGoogle Scholar
  13. 13.
    Bogdan C, Rollinghoff M, Diefenbach A. The role of nitric oxide in innate immunity. Immunol Rev. 2000;173:17–26.PubMedCrossRefGoogle Scholar
  14. 14.
    Mantovani A, Marchesi F, Porta C, Sica A, Allavena P. Inflammation and cancer: breast cancer as a prototype. Breast. 2007;16 Suppl 2:S27–33.PubMedCrossRefGoogle Scholar
  15. 15.
    Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677–86.PubMedCrossRefGoogle Scholar
  16. 16.
    Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124:263–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Gratchev A, Schledzewski K, Guillot P, Goerdt S. Alternatively activated antigen-presenting cells: molecular repertoire, immune regulation, and healing. Skin Pharmacol Appl Skin Physiol. 2001;14:272–9.PubMedGoogle Scholar
  19. 19.
    Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.PubMedCrossRefGoogle Scholar
  20. 20.
    Elgert KD, Alleva DG, Mullins DW. Tumor-induced immune dysfunction: the macrophage connection. J Leukoc Biol. 1998;64:275–90.PubMedGoogle Scholar
  21. 21.
    Pellegrini P, Berghella AM, Del Beato T, Cicia S, Adorno D, Casciani CU. Disregulation in TH1 and TH2 subsets of CD4+ T cells in peripheral blood of colorectal cancer patients and involvement in cancer establishment and progression. Cancer Immunol Immunother. 1996;42:1–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Sheu BC, Lin RH, Lien HC, Ho HN, Hsu SM, Huang SC. Predominant Th2/Tc2 polarity of tumor-infiltrating lymphocytes in human cervical cancer. J Immunol. 2001;167:2972–8.PubMedGoogle Scholar
  23. 23.
    Tatsumi T, Kierstead LS, Ranieri E, Gesualdo L, Schena FP, Finke JH, et al. Disease-associated bias in T helper type 1 (Th1)/Th2 CD4(+) T cell responses against MAGE-6 in HLA-DRB10401(+) patients with renal cell carcinoma or melanoma. J Exp Med. 2002;196:619–28.PubMedCrossRefGoogle Scholar
  24. 24.
    Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG, et al. Macrophage polarization in tumour progression. Semin Cancer Biol. 2008;18:349–55.PubMedCrossRefGoogle Scholar
  25. 25.
    Pearce EJ, Kane CM, Sun J. Regulation of dendritic cell function by pathogen-derived molecules plays a key role in dictating the outcome of the adaptive immune response. Chem Immunol Allergy. 2006;90:82–90.PubMedCrossRefGoogle Scholar
  26. 26.
    Lamhamedi-Cherradi SE, Martin RE, Ito T, Kheradmand F, Corry DB, Liu YJ, et al. Fungal proteases induce Th2 polarization through limited dendritic cell maturation and reduced production of IL-12. J Immunol. 2008;180:6000–9.PubMedGoogle Scholar
  27. 27.
    DeNardo DG, Andreu P, Coussens LM. Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev. 2010;29:309–16.PubMedCrossRefGoogle Scholar
  28. 28.
    Mantovani A. The yin-yang of tumor-associated neutrophils. Cancer Cell. 2009;16:173–4.PubMedCrossRefGoogle Scholar
  29. 29.
    Stout RD, Watkins SK, Suttles J. Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages. J Leukoc Biol. 2009;86:1105–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci. 2008;13:453–61.PubMedCrossRefGoogle Scholar
  31. 31.
    Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51.PubMedCrossRefGoogle Scholar
  32. 32.
    Li J, Zhu H, Chen T, Dai G, Zou L. TGF-beta1 and BRCA2 Expression are Associated with Clinical Factors in Breast Cancer. Cell Biochem Biophys. 2011.Google Scholar
  33. 33.
    Heckel MC, Wolfson A, Slachta CA, Schwarting R, Salgame P, Katsetos CD, et al. Human breast tumor cells express IL-10 and IL-12p40 transcripts and proteins, but do not produce IL-12p70. Cell Immunol. 2011;266:143–53.PubMedCrossRefGoogle Scholar
  34. 34.
    Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169:2756–61.PubMedGoogle Scholar
  35. 35.
    Zou W, Regulatory T. cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6:295–307.PubMedCrossRefGoogle Scholar
  36. 36.
    Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009;139:891–906.PubMedCrossRefGoogle Scholar
  37. 37.
    Duner S, Lopatko Lindman J, Gundewar C, Ansari D, Andersson R. Pancreatic cancer: the role of pancreatic stellate cells in tumor progression. Pancreatology. 2010;10:673–81.PubMedCrossRefGoogle Scholar
  38. 38.
    Egeblad M, Rasch MG, Weaver VM. Dynamic interplay between the collagen scaffold and tumor evolution. Curr Opin Cell Biol. 2010;22:697–706.PubMedCrossRefGoogle Scholar
  39. 39.
    Kaplan G. In vitro differentiation of human monocytes. Monocytes cultured on glass are cytotoxic to tumor cells but monocytes cultured on collagen are not. J Exp Med. 1983;157:2061–72.PubMedCrossRefGoogle Scholar
  40. 40.
    Kaplan G, Gaudernack G. In vitro differentiation of human monocytes. Differences in monocyte phenotypes induced by cultivation on glass or on collagen. J Exp Med. 1982;156:1101–14.PubMedCrossRefGoogle Scholar
  41. 41.
    Verbrugge A, Ruiter Td T, Clevers H, Meyaard L. Differential contribution of the immunoreceptor tyrosine-based inhibitory motifs of human leukocyte-associated Ig-like receptor-1 to inhibitory function and phosphatase recruitment. Int Immunol. 2003;15:1349–58.PubMedCrossRefGoogle Scholar
  42. 42.
    Birge RB, Ucker DS. Innate apoptotic immunity: the calming touch of death. Cell Death Differ. 2008;15:1096–102.PubMedCrossRefGoogle Scholar
  43. 43.
    Leek RD, Hunt NC, Landers RJ, Lewis CE, Royds JA, Harris AL. Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J Pathol. 2000;190:430–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Leek RD, Talks KL, Pezzella F, Turley H, Campo L, Brown NS, et al. Relation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) expression in tumor-infiltrative macrophages to tumor angiogenesis and the oxidative thymidine phosphorylase pathway in Human breast cancer. Cancer Res. 2002;62:1326–9.PubMedGoogle Scholar
  45. 45.
    Sameni M, Dosescu J, Moin K, Sloane BF. Functional imaging of proteolysis: stromal and inflammatory cells increase tumor proteolysis. Mol Imaging. 2003;2:159–75.PubMedCrossRefGoogle Scholar
  46. 46.
    Goswami S, Sahai E, Wyckoff JB, Cammer M, Cox D, Pixley FJ, et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res. 2005;65:5278–83.PubMedCrossRefGoogle Scholar
  47. 47.
    DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, et al. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell. 2009;16:91–102.PubMedCrossRefGoogle Scholar
  48. 48.
    Lin EY, Gouon-Evans V, Nguyen AV, Pollard JW. The macrophage growth factor CSF-1 in mammary gland development and tumor progression. J Mammary Gland Biol Neoplasia. 2002;7:147–62.PubMedCrossRefGoogle Scholar
  49. 49.
    Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 2011;doi: 10.1038/nature10138. [Epub ahead of print].
  50. 50.
    Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Norian LA, Rodriguez PC, O’Mara LA, Zabaleta J, Ochoa AC, Cella M, et al. Tumor-infiltrating regulatory dendritic cells inhibit CD8+ T cell function via L-arginine metabolism. Cancer Res. 2009;69:3086–94.PubMedCrossRefGoogle Scholar
  52. 52.
    Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res. 2005;11:6713–21.PubMedCrossRefGoogle Scholar
  53. 53.
    Bronte V, Serafini P, Apolloni E, Zanovello P. Tumor-induced immune dysfunctions caused by myeloid suppressor cells. J Immunother. 2001;24:431–46.PubMedCrossRefGoogle Scholar
  54. 54.
    Ostrand-Rosenberg S. Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother. 2010;59:1593–600.PubMedCrossRefGoogle Scholar
  55. 55.
    Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol. 2007;179:977–83.PubMedGoogle Scholar
  56. 56.
    Iwamoto M, Shinohara H, Miyamoto A, Okuzawa M, Mabuchi H, Nohara T, et al. Prognostic value of tumor-infiltrating dendritic cells expressing CD83 in human breast carcinomas. Int J Cancer. 2003;104:92–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001;1:135–45.PubMedCrossRefGoogle Scholar
  58. 58.
    Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821–32.PubMedCrossRefGoogle Scholar
  59. 59.
    Klostergaard J, Leroux ME, Ezell SM, Kull Jr FC. Tumoricidal effector mechanisms of murine Bacillus Calmette-Guerin-activated macrophages: mediation of cytolysis, mitochondrial respiration inhibition, and release of intracellular iron by distinct mechanisms. Cancer Res. 1987;47:2014–9.PubMedGoogle Scholar
  60. 60.
    Pryor K, Goddard J, Goldstein D, Stricker P, Russell P, Golovsky D, et al. Bacillus Calmette-Guerin (BCG) enhances monocyte- and lymphocyte-mediated bladder tumour cell killing. Br J Cancer. 1995;71:801–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Fidler IJ, Jessup JM, Fogler WE, Staerkel R, Mazumder A. Activation of tumoricidal properties in peripheral blood monocytes of patients with colorectal carcinoma. Cancer Res. 1986;46:994–8.PubMedGoogle Scholar
  62. 62.
    Turyna B, Jurek A, Gotfryd K, Siaskiewicz A, Kubit P, Klein A. Peritonitis-induced antitumor activity of peritoneal macrophages from uremic patients. Folia Histochem Cytobiol. 2004;42:147–53.PubMedGoogle Scholar
  63. 63.
    Martin-Manso G, Galli S, Ridnour LA, Tsokos M, Wink DA, Roberts DD. Thrombospondin 1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells. Cancer Res. 2008;68:7090–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Wright SE, Khaznadar R, Wang Z, Quinlin IS, Rewers-Felkins KA, Phillips CA, et al. Generation of MUC1-stimulated mononuclear cells using optimized conditions. Scand J Immunol. 2008;67:24–9.PubMedGoogle Scholar
  65. 65.
    Inoue M, Fujii H, Kaseyama H, Yamashina I, Nakada H. Stimulation of macrophages by mucins through a macrophage scavenger receptor. Biochem Biophys Res Commun. 1999;264:276–80.PubMedCrossRefGoogle Scholar
  66. 66.
    Beatson RE, Taylor-Papadimitriou J, Burchell JM. MUC1 immunotherapy. Immunotherapy. 2010;2:305–27.PubMedCrossRefGoogle Scholar
  67. 67.
    Wilbanks GD, Ahn MC, Beck DA, Braun DP. Tumor cytotoxicity of peritoneal macrophages and peripheral blood monocytes from patients with ovarian, endometrial, and cervical cancer. Int J Gynecol Cancer. 1999;9:427–32.PubMedCrossRefGoogle Scholar
  68. 68.
    O’Mahony DS, Pham U, Iyer R, Hawn TR, Liles WC. Differential constitutive and cytokine-modulated expression of human Toll-like receptors in primary neutrophils, monocytes, and macrophages. Int J Med Sci. 2008;5:1–8.PubMedGoogle Scholar
  69. 69.
    Bellora F, Castriconi R, Dondero A, Reggiardo G, Moretta L, Mantovani A, et al. The interaction of human natural killer cells with either unpolarized or polarized macrophages results in different functional outcomes. Proc Natl Acad Sci USA. 2010;107:21659–64.PubMedCrossRefGoogle Scholar
  70. 70.
    Di Carlo E, Forni G, Lollini P, Colombo MP, Modesti A, Musiani P. The intriguing role of polymorphonuclear neutrophils in antitumor reactions. Blood. 2001;97:339–45.PubMedCrossRefGoogle Scholar
  71. 71.
    Rees RC, Mian S. Selective MHC expression in tumours modulates adaptive and innate antitumour responses. Cancer Immunol Immunother. 1999;48:374–81.PubMedCrossRefGoogle Scholar
  72. 72.
    Samarakoon A, Chu H, Malarkannan S. Murine NKG2D ligands: “double, double toil and trouble”. Mol Immunol. 2009;46:1011–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Orr MT, Lanier LL. Natural killer cell education and tolerance. Cell. 2010;142:847–56.PubMedCrossRefGoogle Scholar
  74. 74.
    Chen K, Huang J, Gong W, Iribarren P, Dunlop NM, Wang JM. Toll-like receptors in inflammation, infection and cancer. Int Immunopharmacol. 2007;7:1271–85.PubMedCrossRefGoogle Scholar
  75. 75.
    Curtin JF, Liu N, Candolfi M, Xiong W, Assi H, Yagiz K, et al. HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Med. 2009;6:e10.PubMedCrossRefGoogle Scholar
  76. 76.
    Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13:1050–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Aymeric L, Apetoh L, Ghiringhelli F, Tesniere A, Martins I, Kroemer G, et al. Tumor cell death and ATP release prime dendritic cells and efficient anticancer immunity. Cancer Res. 2010;70:855–8.PubMedCrossRefGoogle Scholar
  78. 78.
    Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med. 2009;15:1170–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Garg AD, Nowis D, Golab J, Vandenabeele P, Krysko DV, Agostinis P. Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation. Biochim Biophys Acta. 2010;1805:53–71.PubMedGoogle Scholar
  80. 80.
    Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13:54–61.PubMedCrossRefGoogle Scholar
  81. 81.
    Chan CW, Housseau F. The ‘kiss of death’ by dendritic cells to cancer cells. Cell Death Differ. 2008;15:58–69.PubMedCrossRefGoogle Scholar
  82. 82.
    MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol. 1997;15:323–50.PubMedCrossRefGoogle Scholar
  83. 83.
    Falschlehner C, Schaefer U, Walczak H. Following TRAIL’s path in the immune system. Immunology. 2009;127:145–54.PubMedCrossRefGoogle Scholar
  84. 84.
    Lechner M, Lirk P, Rieder J. Inducible nitric oxide synthase (iNOS) in tumor biology: the two sides of the same coin. Semin Cancer Biol. 2005;15:277–89.PubMedCrossRefGoogle Scholar
  85. 85.
    Leon-Bollotte L, Subramaniam S, Cauvard O, Plenchette-Colas S, Paul C, Godard C, et al. S-nitrosylation of the death receptor fas promotes fas ligand-mediated apoptosis in cancer cells. Gastroenterology. 2011;140:2009–2018 e4.PubMedCrossRefGoogle Scholar
  86. 86.
    Jaiswal S, Chao MP, Majeti R, Weissman IL. Macrophages as mediators of tumor immunosurveillance. Trends Immunol. 2010;31:212–9.PubMedCrossRefGoogle Scholar
  87. 87.
    Terabe M, Berzofsky JA. The role of NKT cells in tumor immunity. Adv Cancer Res. 2008;101:277–348.PubMedCrossRefGoogle Scholar
  88. 88.
    Taniguchi M, Seino K, Nakayama T. The NKT cell system: bridging innate and acquired immunity. Nat Immunol. 2003;4:1164–5.PubMedCrossRefGoogle Scholar
  89. 89.
    Schietinger A, Philip M, Schreiber H. Specificity in cancer immunotherapy. Semin Immunol. 2008;20:276–85.PubMedCrossRefGoogle Scholar
  90. 90.
    Feng Y, Gao J, Yang M. When MAGE meets RING: insights into biological functions of MAGE proteins. Protein Cell. 2011;2:7–12.PubMedCrossRefGoogle Scholar
  91. 91.
    Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, et al. The consensus coding sequences of human breast and colorectal cancers. Science. 2006;314:268–74.PubMedCrossRefGoogle Scholar
  92. 92.
    Segal NH, Parsons DW, Peggs KS, Velculescu V, Kinzler KW, Vogelstein B, et al. Epitope landscape in breast and colorectal cancer. Cancer Res. 2008;68:889–92.PubMedCrossRefGoogle Scholar
  93. 93.
    Asano K, Nabeyama A, Miyake Y, Qiu CH, Kurita A, Tomura M, et al. CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity. 2011;34:85–95.PubMedCrossRefGoogle Scholar
  94. 94.
    Hicks AM, Riedlinger G, Willingham MC, Alexander-Miller MA, Von Kap-Herr C, Pettenati MJ, et al. Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. Proc Natl Acad Sci USA. 2006;103:7753–8.PubMedCrossRefGoogle Scholar
  95. 95.
    Hoption Cann SA, van Netten JP, van Netten C. Dr William Coley and tumour regression: a place in history or in the future. Postgrad Med J. 2003;79:672–80.PubMedGoogle Scholar
  96. 96.
    Cameron DA, Massie C, Kerr G, Leonard RC. Moderate neutropenia with adjuvant CMF confers improved survival in early breast cancer. Br J Cancer. 2003;89:1837–42.PubMedCrossRefGoogle Scholar
  97. 97.
    Le HK, Graham L, Cha E, Morales JK, Manjili MH, Bear HD. Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. Int Immunopharmacol. 2009;9:900–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Kodumudi KN, Woan K, Gilvary DL, Sahakian E, Wei S, Djeu JY. A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res. 2010;16:4583–94.PubMedCrossRefGoogle Scholar
  99. 99.
    Thompson K, Rogers MJ, Coxon FP, Crockett JC. Cytosolic entry of bisphosphonate drugs requires acidification of vesicles after fluid-phase endocytosis. Mol Pharmacol. 2006;69:1624–32.PubMedCrossRefGoogle Scholar
  100. 100.
    Coleman R, Cook R, Hirsh V, Major P, Lipton A. Zoledronic acid use in cancer patients: more than just supportive care? Cancer. 2011;117:11–23.PubMedCrossRefGoogle Scholar
  101. 101.
    DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, et al. Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy. Cancer Discovery 2011;1:doi: 10.1158/2159-8274.CD-10-0028.
  102. 102.
    De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell. 2005;8:211–26.PubMedCrossRefGoogle Scholar
  103. 103.
    De Palma M, Mazzieri R, Politi LS, Pucci F, Zonari E, Sitia G, et al. Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell. 2008;14:299–311.PubMedCrossRefGoogle Scholar
  104. 104.
    Rosenzwajg M, Jourquin F, Tailleux L, Gluckman JC. CD40 ligation and phagocytosis differently affect the differentiation of monocytes into dendritic cells. J Leukoc Biol. 2002;72:1180–9.PubMedGoogle Scholar
  105. 105.
    Williams P, Bouchentouf M, Rafei M, Romieu-Mourez R, Hsieh J, Boivin MN, et al. A dendritic cell population generated by a fusion of GM-CSF and IL-21 induces tumor-antigen-specific immunity. J Immunol. 2010;185:7358–66.PubMedCrossRefGoogle Scholar
  106. 106.
    Mailliard RB, Wankowicz-Kalinska A, Cai Q, Wesa A, Hilkens CM, Kapsenberg ML, et al. alpha-type-1 polarized dendritic cells: a novel immunization tool with optimized CTL-inducing activity. Cancer Res. 2004;64:5934–7.PubMedCrossRefGoogle Scholar
  107. 107.
    Sun Z, Yao Z, Liu S, Tang H, Yan X. An oligonucleotide decoy for Stat3 activates the immune response of macrophages to breast cancer. Immunobiology. 2006;211:199–209.PubMedCrossRefGoogle Scholar
  108. 108.
    Ostrand-Rosenberg S, Grusby MJ, Clements VK. Cutting edge: STAT6-deficient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma. J Immunol. 2000;165:6015–9.PubMedGoogle Scholar
  109. 109.
    Park JW, Melisko ME, Esserman LJ, Jones LA, Wollan JB, Sims R. Treatment with autologous antigen-presenting cells activated with the HER-2 based antigen Lapuleucel-T: results of a phase I study in immunologic and clinical activity in HER-2 overexpressing breast cancer. J Clin Oncol. 2007;25:3680–7.PubMedCrossRefGoogle Scholar
  110. 110.
    Monnet I, Breau JL, Moro D, Lena H, Eymard JC, Menard O, et al. Intrapleural infusion of activated macrophages and gamma-interferon in malignant pleural mesothelioma: a phase II study. Chest. 2002;121:1921–7.PubMedCrossRefGoogle Scholar
  111. 111.
    Geller MA, Cooley S, Judson PL, Ghebre R, Carson LF, Argenta PA, et al. A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy. 2011;13:98–107.PubMedCrossRefGoogle Scholar
  112. 112.
    Soliman H. Developing an effective breast cancer vaccine. Cancer Control. 2010;17:183–90.PubMedGoogle Scholar
  113. 113.
    Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411–22.PubMedCrossRefGoogle Scholar
  114. 114.
    Jahnisch H, Fussel S, Kiessling A, Wehner R, Zastrow S, Bachmann M, et al. Dendritic cell-based immunotherapy for prostate cancer. Clin Dev Immunol. 2010;2010:517493.PubMedCrossRefGoogle Scholar
  115. 115.
    Porcheray F, Viaud S, Rimaniol AC, Leone C, Samah B, Dereuddre-Bosquet N, et al. Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol. 2005;142:481–9.PubMedGoogle Scholar
  116. 116.
    Stout RD, Jiang C, Matta B, Tietzel I, Watkins SK, Suttles J. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol. 2005;175:342–9.PubMedGoogle Scholar
  117. 117.
    Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007;445:656–60.PubMedCrossRefGoogle Scholar
  118. 118.
    Guerriero JL, Ditsworth D, Catanzaro JM, Sabino G, Furie MB, Kew RR, et al. DNA alkylating therapy induces tumor regression through an HMGB1-mediated activation of innate immunity. J Immunol. 2011;186:3517–26.PubMedCrossRefGoogle Scholar
  119. 119.
    Ahn GO, Tseng D, Liao CH, Dorie MJ, Czechowicz A, Brown JM. Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proc Natl Acad Sci USA. 2010;107:8363–8.PubMedCrossRefGoogle Scholar
  120. 120.
    Zhang W, Zhu XD, Sun HC, Xiong YQ, Zhuang PY, Xu HX, et al. Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin Cancer Res. 2010;16:3420–30.PubMedCrossRefGoogle Scholar
  121. 121.
    Rausch MP, Hahn T, Ramanathapuram L, Bradley-Dunlop D, Mahadevan D, Mercado-Pimentel ME, et al. An orally active small molecule TGF-beta receptor I antagonist inhibits the growth of metastatic murine breast cancer. Anticancer Res. 2009;29:2099–109.PubMedGoogle Scholar
  122. 122.
    Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell. 2009;16:183–94.PubMedCrossRefGoogle Scholar
  123. 123.
    Barnett BG, Ruter J, Kryczek I, Brumlik MJ, Cheng PJ, Daniel BJ, et al. Regulatory T cells: a new frontier in cancer immunotherapy. Adv Exp Med Biol. 2008;622:255–60.PubMedCrossRefGoogle Scholar
  124. 124.
    Okada C, Akbar SM, Horiike N, Onji M. Early development of primary biliary cirrhosis in female C57BL/6 mice because of poly I:C administration. Liver Int. 2005;25:595–603.PubMedCrossRefGoogle Scholar
  125. 125.
    Hsu RY, Chan CH, Spicer JD, Rousseau MC, Giannias B, Rousseau S, et al. LPS-Induced TLR4 Signaling in Human Colorectal Cancer Cells Increases {beta}1 Integrin-Mediated Cell Adhesion and Liver Metastasis. Cancer Res. 2011;71:1989–98.PubMedCrossRefGoogle Scholar
  126. 126.
    Zaks K, Jordan M, Guth A, Sellins K, Kedl R, Izzo A, et al. Efficient immunization and cross-priming by vaccine adjuvants containing TLR3 or TLR9 agonists complexed to cationic liposomes. J Immunol. 2006;176:7335–45.PubMedGoogle Scholar
  127. 127.
    Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev Cancer. 2009;9:285–93.PubMedCrossRefGoogle Scholar
  128. 128.
    Killion JJ, Fidler IJ. Therapy of cancer metastasis by tumoricidal activation of tissue macrophages using liposome-encapsulated immunomodulators. Pharmacol Ther. 1998;78:141–54.PubMedCrossRefGoogle Scholar
  129. 129.
    Vyas SP, Goyal AK, Khatri K. Mannosylated liposomes for targeted vaccines delivery. Methods Mol Biol. 2010;605:177–88.PubMedCrossRefGoogle Scholar
  130. 130.
    Matsui M, Shimizu Y, Kodera Y, Kondo E, Ikehara Y, Nakanishi H. Targeted delivery of oligomannose-coated liposome to the omental micrometastasis by peritoneal macrophages from patients with gastric cancer. Cancer Sci. 2010;101:1670–7.PubMedCrossRefGoogle Scholar
  131. 131.
    Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331:1612–6.PubMedCrossRefGoogle Scholar
  132. 132.
    Tanaka H, Matsushima H, Mizumoto N, Takashima A. Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells. Cancer Res. 2009;69:6978–86.PubMedCrossRefGoogle Scholar
  133. 133.
    Guiducci C, Vicari AP, Sangaletti S, Trinchieri G, Colombo MP. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res. 2005;65:3437–46.PubMedGoogle Scholar
  134. 134.
    Berraondo P, Nouze C, Preville X, Ladant D, Leclerc C. Eradication of large tumors in mice by a tritherapy targeting the innate, adaptive, and regulatory components of the immune system. Cancer Res. 2007;67:8847–55.PubMedCrossRefGoogle Scholar
  135. 135.
    Helms MW, Prescher JA, Cao YA, Schaffert S, Contag CH. IL-12 enhances efficacy and shortens enrichment time in cytokine-induced killer cell immunotherapy. Cancer Immunol Immunother. 2010;59:1325–34.PubMedCrossRefGoogle Scholar
  136. 136.
    Eisenring M, vom Berg J, Kristiansen G, Saller E, Becher B. IL-12 initiates tumor rejection via lymphoid tissue-inducer cells bearing the natural cytotoxicity receptor NKp46. Nat Immunol. 2010;11:1030–8.PubMedCrossRefGoogle Scholar
  137. 137.
    Albini A, Brigati C, Ventura A, Lorusso G, Pinter M, Morini M, et al. Angiostatin anti-angiogenesis requires IL-12: the innate immune system as a key target. J Transl Med. 2009;7:5.PubMedCrossRefGoogle Scholar
  138. 138.
    Egeblad M, Ewald AJ, Askautrud HA, Truitt ML, Welm BE, Bainbridge E, et al. Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy. Dis Model Mech. 2008;1:155–67.PubMedCrossRefGoogle Scholar
  139. 139.
    Ishii T, Ishii M. Intravital two-photon imaging: a versatile tool for dissecting the immune system. Ann Rheum Dis. 2011;70 Suppl 1:i113–5.PubMedCrossRefGoogle Scholar
  140. 140.
    Fukumura D, Duda DG, Munn LL, Jain RK. Tumor microvasculature and microenvironment: novel insights through intravital imaging in pre-clinical models. Microcirculation. 2010;17:206–25.PubMedCrossRefGoogle Scholar
  141. 141.
    Breart B, Lemaitre F, Celli S, Bousso P. Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice. J Clin Invest. 2008;118:1390–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Cold Spring Harbor LaboratoryCold Spring HarborUSA

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