Cancer and Metastasis Reviews

, Volume 26, Issue 3–4, pp 373–400 | Cite as

Inflammatory cell infiltration of tumors: Jekyll or Hyde



Inflammatory cell infiltration of tumors contributes either positively or negatively to tumor invasion, growth, metastasis, and patient outcomes, creating a Dr. Jekyll or Mr. Hyde conundrum when examining mechanisms of action. This is due to tumor heterogeneity and the diversity of the inflammatory cell phenotypes that infiltrate primary and metastatic lesions. Tumor infiltration by macrophages is generally associated with neoangiogenesis and negative outcomes, whereas dendritic cell (DC) infiltration is typically associated with a positive clinical outcome in association with their ability to present tumor antigens (Ags) and induce Ag-specific T cell responses. Myeloid-derived suppressor cells (MDSCs) also infiltrate tumors, inhibiting immune responses and facilitating tumor growth and metastasis. In contrast, T cell infiltration of tumors provides a positive prognostic surrogate, although subset analyses suggest that not all infiltrating T cells predict a positive outcome. In general, infiltration by CD8+ T cells predicts a positive outcome, while CD4+ cells predict a negative outcome. Therefore, the analysis of cellular phenotypes and potentially spatial distribution of infiltrating cells are critical for an accurate assessment of outcome. Similarly, cellular infiltration of metastatic foci is also a critical parameter for inducing therapeutic responses, as well as establishing tumor dormancy. Current strategies for cellular, gene, and molecular therapies are focused on the manipulation of infiltrating cellular populations. Within this review, we discuss the role of tumor infiltrating, myeloid-monocytic cells, and T lymphocytes, as well as their potential for tumor control, immunosuppression, and facilitation of metastasis.


Macrophage Tumor infiltration Myeloid-derived suppressor cell Dendritic cell T lymphocyte Prognostic surrogate 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Sadler, T. E., Jones, D. E., & Castro, J. E. (1977). The effects of altered phagocytic activity on growth of primary and metastatic tumor. In K. James, J. B. McBride, & A. Stuart (Eds.), The macrophage and cancer (pp. 155–63). Edinburgh: Econoprint.Google Scholar
  2. 2.
    Mantovani, A., Giavazzi, R., Polentarutti, N., Spreafico, F., & Garattini, S. (1980). Divergent effects of macrophage toxins on growth of primary tumors and lung metastases in mice. International Journal of Cancer, 25, 617–20.CrossRefGoogle Scholar
  3. 3.
    Den Otter, W. F., & Dullens, F. J. (1977). Anti-tumor effects of macrophages injected into animals: A review. In K. James, B. McBride, & A. Staurt (Eds.), The macrophage and cancer (pp. 119–41). Edinburgh: Econoprint.Google Scholar
  4. 4.
    Fidler, I. J. (1974). Inhibition of pulmonary metastasis by intravenous injection of specifically activated macrophages. Cancer Research, 34, 1074–078.PubMedGoogle Scholar
  5. 5.
    Liotta, L. A., Gattozzi, C., Kleinerman, J., & Saidel, G. (1977). Reduction of tumour cell entry into vessels by BCG-activated macrophages. British Journal of Cancer, 36, 639–41.PubMedGoogle Scholar
  6. 6.
    Mantovani, A. (1978). Effects on in vitro tumor growth of murine macrophages isolated from sarcoma lines differing in immunogenicity and metastasizing capacity. International Journal of Cancer, 22, 741–46.CrossRefGoogle Scholar
  7. 7.
    Sombroek, C. C., Stam, A. G., Masterson, A. J., Lougheed, S. M., Schakel, M. J., Meijer, C. J., et al. (2002). Prostanoids play a major role in the primary tumor-induced inhibition of dendritic cell differentiation. Journal of Immunology, 168, 4333–343.Google Scholar
  8. 8.
    Kusmartsev, S., & Gabrilovich, D. I. (2003). Inhibition of myeloid cell differentiation in cancer: The role of reactive oxygen species. Journal of Leukocyte Biology, 74, 186–96.PubMedCrossRefGoogle Scholar
  9. 9.
    Candido, K. A., Shimizu, K., McLaughlin, J. C., Kunkel, R., Fuller, J. A., Redman, B. G., et al. (2001). Local administration of dendritic cells inhibits established breast tumor growth: Implications for apoptosis-inducing agents. Cancer Research, 61, 228–36.PubMedGoogle Scholar
  10. 10.
    Timar, J., Ladanyi, A., Forster-Horvath, C., Lukits, J., Dome, B., Remenar, E., et al. (2005). Neoadjuvant immunotherapy of oral squamous cell carcinoma modulates intratumoral CD4/CD8 ratio and tumor microenvironment: A multicenter phase II clinical trial. Journal of Clinical Oncology, 23, 3421–432.PubMedCrossRefGoogle Scholar
  11. 11.
    Triozzi, P. L., Khurram, R., Aldrich, W. A., Walker, M. J., Kim, J. A., & Jaynes, S. (2000). Intratumoral injection of dendritic cells derived in vitro in patients with metastatic cancer. Cancer, 89, 2646–654.PubMedCrossRefGoogle Scholar
  12. 12.
    Fidler, I. J., Roblin, R. O., & Poste, G. (1978). In vitro tumoricidal activity of macrophages against virus-transformed lines with temperature-dependent transformed phenotypic characteristics. Cellular Immunology, 38, 131–46.PubMedCrossRefGoogle Scholar
  13. 13.
    Sone, S., & Fidler, I. J. (1981). Activation of rat alveolar macrophages to the tumoricidal state in the presence of progressively growing pulmonary metastases. Cancer Research, 41, 2401–406.PubMedGoogle Scholar
  14. 14.
    Key, M. E., Talmadge, J. E., Fogler, W. E., Bucana, C., & Fidler, I. J. (1982). Isolation of tumoricidal macrophages from lung melanoma metastases of mice treated systemically with liposomes containing a lipophilic derivative of muramyl dipeptide. Journal of the National Cancer Institute, 69, 1198.PubMedGoogle Scholar
  15. 15.
    Ross, J., & Auger, M. (2002). The biology of the macrophage. In B. Burke & C. Lewis (Eds.), The macrophage (2nd ed.). Oxford: Oxford University Press.Google Scholar
  16. 16.
    Mantovani, A., Sica, A., Sozzani, S., Allavena, P., Vecchi, A., & Locati, M. (2004). The chemokine system in diverse forms of macrophage activation and polarization. Trends in Immunology, 25, 677–86.PubMedCrossRefGoogle Scholar
  17. 17.
    Coffman, R. L. (2006). Origins of the T(H)1’T(H)2 model: A personal perspective. Nature Immunology, 7, 539–41.PubMedCrossRefGoogle Scholar
  18. 18.
    Balkwill, F., Charles, K. A., & Mantovani, A. (2005). Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cells, 7, 211–17.CrossRefGoogle Scholar
  19. 19.
    Mantovani, A., Sica, A., & Locati, M. (2007). New vistas on macrophage differentiation and activation. European Journal of Immunology, 37, 14–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Ghassabeh, G. H., de Baetselier P., Brys, L., Noel, W., van Ginderachter, J. A., Meerschaut, S., et al. (2006). Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo in different pathologic conditions. Blood, 108, 575–83.PubMedCrossRefGoogle Scholar
  21. 21.
    Verreck, F. A., de Boer T., Langenberg, D. M., Hoeve, M. A., Kramer, M., Vaisberg, E., et al. (2004). Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proceedings of the National Academy of Sciences of the United States of America, 101, 4560–565.PubMedCrossRefGoogle Scholar
  22. 22.
    Mantovani, A. (1999). The chemokine system: Redundancy for robust outputs. Immunology Today, 20, 254–57.PubMedCrossRefGoogle Scholar
  23. 23.
    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 in Immunology, 23, 549–55.PubMedCrossRefGoogle Scholar
  24. 24.
    Gordon, S. (2003). Alternative activation of macrophages. Nature Reviews Immunology, 3, 23–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Anderson, C. F., & Mosser, D. M. (2002). A novel phenotype for an activated macrophage: The type 2 activated macrophage. Journal of Leukocyte Biology, 72, 101–06.PubMedGoogle Scholar
  26. 26.
    Elgert, K. D., Alleva, D. G., & Mullins, D. W. (1998). Tumor-induced immune dysfunction: The macrophage connection. Journal of Leukocyte Biology, 64, 275–90.PubMedGoogle Scholar
  27. 27.
    Eccles, S. A., & Alexander, P. (1974). Macrophage content of tumours in relation to metastatic spread and host immune reaction. Nature, 250, 667–69.PubMedCrossRefGoogle Scholar
  28. 28.
    Gauci, G., & Alexander, P. (1975). The macrophage content of some human tumors. Cancer Letters, 1, 29.PubMedCrossRefGoogle Scholar
  29. 29.
    Talmadge, J. E., Key, M., & Fidler, I. J. (1981). Macrophage content of metastatic and nonmetastatic rodent neoplasms. Journal of Immunology, 126, 2245–248.Google Scholar
  30. 30.
    Evans, R., & Lawler, E. M. (1980). Macrophage content and immunogenicity of C57BL/6J and BALB/cByJ methylcholanthrene-induced sarcomas. International Journal of Cancer, 26, 831–35.CrossRefGoogle Scholar
  31. 31.
    Key, M., Talmadge, J. E., & Fidler, I. J. (1982). Lack of correlation between the progressive growth of spontaneous metastases and their content of infiltrating macrophages. Journal of the Reticuloendothelial Society, 32, 387–96.PubMedGoogle Scholar
  32. 32.
    Kripke, M. L. (1974). Antigenicity of murine skin tumors induced by ultraviolet light. Journal of the National Cancer Institute, 53, 1333–336.PubMedGoogle Scholar
  33. 33.
    Kripke, M. L., & Fisher, M. S. (1976). Immunologic parameters of ultraviolet carcinogenesis. Journal of the National Cancer Institute, 57, 211–15.PubMedGoogle Scholar
  34. 34.
    Lill, P. H., & Fortner, G. W. (1978). Identification and cytotoxic reactivity of inflammatory cells recovered from progressing or regressing syngeneic UV-induced murine tumors. Journal of Immunology, 121, 1854–860.Google Scholar
  35. 35.
    Pross, H. F., & Kerbel, R. S. (1976). An assessment of intratumor phagocytic and surface marker-bearing cells in a series of autochthonous and early passaged chemically induced murine sarcomas. Journal of the National Cancer Institute, 57, 1157–167.PubMedGoogle Scholar
  36. 36.
    Steele, R. J., Eremin, O., Brown, M., & Hawkins, R. A. (1984). A high macrophage content in human breast cancer is not associated with favourable prognostic factors. British Journal of Surgery, 71, 456–58.PubMedCrossRefGoogle Scholar
  37. 37.
    Sun, X. F., & Zhang, H. (2006). Clinicopathological significance of stromal variables: Angiogenesis, lymphangiogenesis, inflammatory infiltration, MMP and PINCH in colorectal carcinomas. Molecular Cancer, 5, 43.PubMedCrossRefGoogle Scholar
  38. 38.
    Fidler, I. J., Schackert, G., Zhang, R. D., Radinsky, R., & Fujimaki, T. (1999). The biology of melanoma brain metastasis. Cancer and Metastasis Reviews, 18, 387–00.PubMedCrossRefGoogle Scholar
  39. 39.
    Talmadge, J. E. (1983). The selective nature of metastasis. Cancer and Metastasis Reviews, 2, 25–0.PubMedCrossRefGoogle Scholar
  40. 40.
    Fidler, I. J., & Talmadge, J. E. (1986). Evidence that intravenously derived murine pulmonary melanoma metastases can originate from the expansion of a single tumor cell. Cancer Research, 46, 5167–171.PubMedGoogle Scholar
  41. 41.
    Fidler, I. J. (1978). Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Research, 38, 2651–660.PubMedGoogle Scholar
  42. 42.
    Nash, J. R., Price, J. E., & Tarin, D. (1981). Macrophage content and colony-forming potential in mouse mammary carcinomas. British Journal of Cancer, 43, 478–85.PubMedGoogle Scholar
  43. 43.
    Alexander, P., Eccles, S. A., & Gauci, C. L. (1976). The significance of macrophages in human and experimental tumors. Annals of the New York Academy of Sciences, 276, 124–33.PubMedCrossRefGoogle Scholar
  44. 44.
    Sunderkotter, C., Beil, W., Roth, J., & Sorg, C. (1991). Cellular events associated with inflammatory angiogenesis in the mouse cornea. American Journal of Pathology, 138, 931–39.PubMedGoogle Scholar
  45. 45.
    Murdoch, C., Giannoudis, A., & Lewis, C. E. (2004). Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood, 104, 2224–234.PubMedCrossRefGoogle Scholar
  46. 46.
    Carmeliet, P., & Jain, R. K. (2000). Angiogenesis in cancer and other diseases. Nature, 407, 249–57.PubMedCrossRefGoogle Scholar
  47. 47.
    Brigati, C., Noonan, D. M., Albini, A., & Benelli, R. (2002). Tumors and inflammatory infiltrates: Friends or foes? Clinical & Experimental Metastasis, 19, 247–58.CrossRefGoogle Scholar
  48. 48.
    Gallucci, S., & Matzinger, P. (2001). Danger signals: SOS to the immune system. Current Opinion in Immunology, 13, 114–19.PubMedCrossRefGoogle Scholar
  49. 49.
    Sher, A., Pearce, E., & Kaye, P. (2003). Shaping the immune response to parasites: Role of dendritic cells. Current Opinion in Immunology, 15, 421–29.PubMedCrossRefGoogle Scholar
  50. 50.
    Nakao, S., Kuwano, T., Tsutsumi-Miyahara, C., Ueda, S., Kimura, Y. N., Hamano, S., et al. (2005). Infiltration of COX-2-expressing macrophages is a prerequisite for IL-1 beta-induced neovascularization and tumor growth. Journal of Clinical Investigation, 115, 2979–991.PubMedCrossRefGoogle Scholar
  51. 51.
    Lewis, C. E., Leek, R., Harris, A., & McGee, J. O. (1995). Cytokine regulation of angiogenesis in breast cancer: The role of tumor-associated macrophages. Journal of Leukocyte Biology, 57, 747–51.PubMedGoogle Scholar
  52. 52.
    Klimp, A. H., Hollema, H., Kempinga, C., van der Zee, A. G., de Vries, E. G., & Daemen, T. (2001). Expression of cyclooxygenase-2 and inducible nitric oxide synthase in human ovarian tumors and tumor-associated macrophages. Cancer Research, 61, 7305–309.PubMedGoogle Scholar
  53. 53.
    Lewis, C. E., & Pollard, J. W. (2006). Distinct role of macrophages in different tumor microenvironments. Cancer Research, 66, 605–12.PubMedCrossRefGoogle Scholar
  54. 54.
    Leek, R. D., Lewis, C. E., Whitehouse, R., Greenall, M., Clarke, J., & Harris, A. L. (1996). Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Research, 56, 4625–629.PubMedGoogle Scholar
  55. 55.
    Hanada, T., Nakagawa, M., Emoto, A., Nomura, T., Nasu, N., & Nomura, Y. (2000). Prognostic value of tumor-associated macrophage count in human bladder cancer. International Journal of Urology, 7, 263–69.PubMedCrossRefGoogle Scholar
  56. 56.
    Lissbrant, I. F., Stattin, P., Wikstrom, P., Damber, J. E., Egevad, L., & Bergh, A. (2000). Tumor associated macrophages in human prostate cancer: Relation to clinicopathological variables and survival. International Journal of Oncology, 17, 445–51.PubMedGoogle Scholar
  57. 57.
    Leek, R. D., Talks, K. L., Pezzella, F., Turley, H., Campo, L., Brown, N. S., et al. (2002). 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 Research, 62, 1326–329.PubMedGoogle Scholar
  58. 58.
    Leek, R. D., Landers, R. J., Harris, A. L., & Lewis, C. E. (1999). Necrosis correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast. British Journal of Cancer, 79, 991–95.PubMedCrossRefGoogle Scholar
  59. 59.
    Burton, J. L., Wells, J. M., Corke, K. P., Maitland, N., Hamdy, F. C., & Lewis, C. E. (2000). Macrophages accumulate in avascular, hypoxic areas of prostate tumors: Implications for the targeted therapeutic gene delivery to such sites. Journal of Pathology, 19, 8A.Google Scholar
  60. 60.
    Lewis, J. S., Landers, R. J., Underwood, J. C., Harris, A. L., & Lewis, C. E. (2000). Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. Journal of Pathology, 192, 150–58.PubMedCrossRefGoogle Scholar
  61. 61.
    Shi, Q., Xiong, Q., Le, X., & Xie, K. (2001). Regulation of interleukin-8 expression by tumor-associated stress factors. Journal of Interferon & Cytokine Research, 21, 553–66.CrossRefGoogle Scholar
  62. 62.
    Chen, J. J., Yao, P. L., Yuan, A., Hong, T. M., Shun, C. T., Kuo, M. L., et al. (2003). Up-regulation of tumor interleukin-8 expression by infiltrating macrophages: Its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer. Clinical Cancer Research, 9, 729–37.PubMedGoogle Scholar
  63. 63.
    Varney, M. L., Olsen, K. J., Mosley, R. L., Bucana, C. D., Talmadge, J. E., & Singh, R. K. (2002). Monocyte/macrophage recruitment, activation and differentiation modulate interleukin-8 production: A paracrine role of tumor-associated macrophages in tumor angiogenesis. In Vivo, 16, 471–77.PubMedGoogle Scholar
  64. 64.
    Watanabe, T., Kawano, Y., Kanamaru, S., Onishi, T., Kaneko, S., Wakata, Y., et al. (1999). Endogenous interleukin-8 (IL-8) surge in granulocyte colony-stimulating factor-induced peripheral blood stem cell mobilization. Blood, 93, 1157–163.PubMedGoogle Scholar
  65. 65.
    Fujimoto, J., Sakaguchi, H., Aoki, I., & Tamaya, T. (2000). Clinical implications of expression of interleukin 8 related to angiogenesis in uterine cervical cancers. Cancer Research, 60, 2632–635.PubMedGoogle Scholar
  66. 66.
    Leek, R. D., Hunt, N. C., Landers, R. J., Lewis, C. E., Royds, J. A., & Harris, A. L. (2000). Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. Journal of Pathology, 190, 430–36.PubMedCrossRefGoogle Scholar
  67. 67.
    Orre, M., & Rogers, P. A. (1999). Macrophages and microvessel density in tumors of the ovary. Gynecologic Oncology, 73, 47–0.PubMedCrossRefGoogle Scholar
  68. 68.
    Nishie, A., Ono, M., Shono, T., Fukushi, J., Otsubo, M., Onoue, H., et al. (1999). Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clinical Cancer Research, 5, 1107–113.PubMedGoogle Scholar
  69. 69.
    Vicioso, L., Gonzalez, F. J., Alvarez, M., Ribelles, N., Molina, M., Marquez, A., et al. (2006). Elevated serum levels of vascular endothelial growth factor are associated with tumor-associated macrophages in primary breast cancer. American Journal of Clinical Pathology, 125, 111–18.PubMedGoogle Scholar
  70. 70.
    Spadaro, M., Ambrosino, E., Iezzi, M., Di, C. E., Sacchetti, P., Curcio, C., et al. (2005). Cure of mammary carcinomas in Her-2 transgenic mice through sequential stimulation of innate (neoadjuvant interleukin-12) and adaptive (DNA vaccine electroporation) immunity. Clinical Cancer Research, 11, 1941–952.PubMedCrossRefGoogle Scholar
  71. 71.
    Kurzawa, H., Wysocka, M., Aruga, E., Chang, A. E., Trinchieri, G., & Lee, W. M. (1998). Recombinant interleukin 12 enhances cellular immune responses to vaccination only after a period of suppression. Cancer Research, 58, 491–99.PubMedGoogle Scholar
  72. 72.
    Brunda, M. J., Luistro, L., Warrier, R. R., Wright, R. B., Hubbard, B. R., Murphy, M., et al. (1993). Antitumor and antimetastatic activity of interleukin-12 against murine tumors. Journal of Experimental Medicine, 178, 1223–230.PubMedCrossRefGoogle Scholar
  73. 73.
    Nastala, C. L., Edington, H. D., McKinney, T. G., Tahara, H., Nalesnik, M. A., Brunda, M. J., et al. (1994). Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production. Journal of Immunology, 153, 1697–706.Google Scholar
  74. 74.
    Jackson, J. D., Yan, Y., Brunda, M. J., Kelsey, L. S., & Talmadge, J. E. (1995). Interleukin-12 enhances peripheral hematopoiesis in vivo. Blood, 85, 2371–376.PubMedGoogle Scholar
  75. 75.
    Belardelli, F., & Ferrantini, M. (2002). Cytokines as a link between innate and adaptive antitumor immunity. Trends in Immunology, 23, 201–08.PubMedCrossRefGoogle Scholar
  76. 76.
    Tsung, K., Dolan, J. P., Tsung, Y. L., & Norton, J. A. (2002). Macrophages as effector cells in interleukin 12-induced T cell-dependent tumor rejection. Cancer Research, 62, 5069–075.PubMedGoogle Scholar
  77. 77.
    Voest, E. E., Kenyon, B. M., O’Reilly, M. S., Truitt, G., D’Amato, R. J., & Folkman, J. (1995). Inhibition of angiogenesis in vivo by interleukin 12. Journal of the National Cancer Institute, 87, 581–86.PubMedCrossRefGoogle Scholar
  78. 78.
    Strasly, M., Cavallo, F., Geuna, M., Mitola, S., Colombo, M. P., Forni, G., et al. (2001). IL-12 inhibition of endothelial cell functions and angiogenesis depends on lymphocyte-endothelial cell cross-talk. Journal of Immunology, 166, 3890–899.Google Scholar
  79. 79.
    Inoue, Y., Nakayama, Y., Minagawa, N., Katsuki, T., Nagashima, N., Matsumoto, K., et al. (2005). Relationship between interleukin-12-expressing cells and antigen-presenting cells in patients with colorectal cancer. Anticancer Research, 25, 3541–546.PubMedGoogle Scholar
  80. 80.
    Wahl, L. M., & Kleinman, H. K. (1998). Tumor-associated macrophages as targets for cancer therapy. Journal of the National Cancer Institute, 90, 1583–584.PubMedCrossRefGoogle Scholar
  81. 81.
    Coughlin, C. M., Salhany, K. E., Wysocka, M., Aruga, E., Kurzawa, H., Chang, A. E., et al. (1998). Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis. Journal of Clinical Investigation, 101, 1441–452.PubMedCrossRefGoogle Scholar
  82. 82.
    Mitola, S., Strasly, M., Prato, M., Ghia, P., & Bussolino, F. (2003). IL-12 regulates an endothelial cell-lymphocyte network: Effect on metalloproteinase-9 production. Journal of Immunology, 171, 3725–733.Google Scholar
  83. 83.
    Egilmez, N. K., Jong, Y. S., Sabel, M. S., Jacob, J. S., Mathiowitz, E., & Bankert, R. B. (2000). In situ tumor vaccination with interleukin-12-encapsulated biodegradable microspheres: Induction of tumor regression and potent antitumor immunity. Cancer Research, 60, 3832–837.PubMedGoogle Scholar
  84. 84.
    Trinchieri, G. (1998). Interleukin-12: A cytokine at the interface of inflammation and immunity. Advances in Immunology, 70, 83–43.PubMedCrossRefGoogle Scholar
  85. 85.
    Dias, S., Boyd, R., & Balkwill, F. (1998). IL-12 regulates VEGF and MMPs in a murine breast cancer model. International Journal of Cancer, 78, 361–65.CrossRefGoogle Scholar
  86. 86.
    Lotze, M. T., Zitvogel, L., Campbell, R., Robbins, P. D., Elder, E., Haluszczak, C., et al. (1996). Cytokine gene therapy of cancer using interleukin-12: Murine and clinical trials. Annals of the New York Academy of Sciences, 795, 440–54.PubMedCrossRefGoogle Scholar
  87. 87.
    van Herpen, C. M., Looman, M., Zonneveld, M., Scharenborg, N., de Wilde, P. C., van de Locht, L., et al. (2004). Intratumoral administration of recombinant human interleukin 12 in head and neck squamous cell carcinoma patients elicits a T-helper 1 profile in the locoregional lymph nodes. Clinical Cancer Research, 10, 2626–635.PubMedCrossRefGoogle Scholar
  88. 88.
    Gollob, J. A., Veenstra, K. G., Parker, R. A., Mier, J. W., McDermott, D. F., Clancy, D., et al. (2003). Phase I trial of concurrent twice-weekly recombinant human interleukin-12 plus low-dose IL-2 in patients with melanoma or renal cell carcinoma. Journal of Clinical Oncology, 21, 2564–573.PubMedCrossRefGoogle Scholar
  89. 89.
    Caruso, M., Pham-Nguyen, K., Kwong, Y. L., Xu, B., Kosai, K. I., Finegold, M., et al. (1996). Adenovirus-mediated interleukin-12 gene therapy for metastatic colon carcinoma. Proceedings of the National Academy of Sciences of the United States of America, 93, 11302–1306.PubMedCrossRefGoogle Scholar
  90. 90.
    Gambotto, A., Tuting, T., McVey, D. L., Kovesdi, I., Tahara, H., Lotze, M. T., et al. (1999). Induction of antitumor immunity by direct intratumoral injection of a recombinant adenovirus vector expressing interleukin-12. Cancer Gene Therapy, 6, 45–3.PubMedCrossRefGoogle Scholar
  91. 91.
    Lin, E. Y., Nguyen, A. V., Russell, R. G., & Pollard, J. W. (2001). Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. Journal of Experimental Medicine, 193, 727–40.PubMedCrossRefGoogle Scholar
  92. 92.
    Hagemann, T., Robinson, S. C., Schulz, M., Trumper, L., Balkwill, F. R., & Binder, C. (2004). Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteases. Carcinogenesis, 25, 1543–549.PubMedCrossRefGoogle Scholar
  93. 93.
    Tsutsui, S., Yasuda, K., Suzuki, K., Tahara, K., Higashi, H., & Era, S. (2005). Macrophage infiltration and its prognostic implications in breast cancer: The relationship with VEGF expression and microvessel density. Oncology Reports, 14, 425–31.PubMedGoogle Scholar
  94. 94.
    Hamada, I., Kato, M., Yamasaki, T., Iwabuchi, K., Watanabe, T., Yamada, T., et al. (2002). Clinical effects of tumor-associated macrophages and dendritic cells on renal cell carcinoma. Anticancer Research, 22, 4281–284.PubMedGoogle Scholar
  95. 95.
    Lewis, C., & Murdoch, C. (2005). Macrophage responses to hypoxia: Implications for tumor progression and anti-cancer therapies. American Journal of Pathology, 167, 627–35.PubMedGoogle Scholar
  96. 96.
    Steinman, R. M., & Witmer, M. D. (1978). Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction in mice. Proceedings of the National Academy of Sciences of the United States of America, 75, 5132–136.PubMedCrossRefGoogle Scholar
  97. 97.
    Ardavin, C., Amigorena, S., & Reis e Sousa. (2004). Dendritic cells: Immunobiology and cancer immunotherapy. Immunity, 20, 17–3.PubMedCrossRefGoogle Scholar
  98. 98.
    Steinman, R. M., Hawiger, D., & Nussenzweig, M. C. (2003). Tolerogenic dendritic cells. Annual Review of Immunology, 21, 685–11.PubMedCrossRefGoogle Scholar
  99. 99.
    Shortman, K., & Liu, Y. J. (2002). Mouse and human dendritic cell subtypes. Nature Reviews Immunology, 2, 151–61.PubMedCrossRefGoogle Scholar
  100. 100.
    Akira, S., & Takeda, K. (2004). Toll-like receptor signalling. Nature Reviews Immunology, 4, 499–11.PubMedCrossRefGoogle Scholar
  101. 101.
    Reis e Sousa. (2004). Toll-like receptors and dendritic cells: For whom the bug tolls. Seminars in Immunology, 16, 27–4.PubMedCrossRefGoogle Scholar
  102. 102.
    Kaisho, T., & Akira, S. (2003). Regulation of dendritic cell function through toll-like receptors. Current Molecular Medicine, 3, 759–71.PubMedCrossRefGoogle Scholar
  103. 103.
    Shortman, K., & Liu, Y. J. (2002). Mouse and human dendritic cell subtypes. Nature Reviews Immunology, 2, 151–61.PubMedCrossRefGoogle Scholar
  104. 104.
    Pulendran, B. (2005). Variegation of the immune response with dendritic cells and pathogen recognition receptors. Journal of Immunology, 174, 2457–465.Google Scholar
  105. 105.
    Kadowaki, N., Ho, S., Antonenko, S., Malefyt, R. W., Kastelein, R. A., Bazan, F., et al. (2001). Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. Journal of Experimental Medicine, 194, 863–69.PubMedCrossRefGoogle Scholar
  106. 106.
    Asselin-Paturel, C., & Trinchieri, G. (2005). Production of type I interferons: Plasmacytoid dendritic cells and beyond. Journal of Experimental Medicine, 202, 461–65.PubMedCrossRefGoogle Scholar
  107. 107.
    Blasius, A. L., & Colonna, M. (2006). Sampling and signaling in plasmacytoid dendritic cells: The potential roles of Siglec-H. Trends in Immunology, 27, 255–60.PubMedCrossRefGoogle Scholar
  108. 108.
    Sallusto, F., Cella, M., Danieli, C., & Lanzavecchia, A. (1995). Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: Downregulation by cytokines and bacterial products. Journal of Experimental Medicine, 182, 389–00.PubMedCrossRefGoogle Scholar
  109. 109.
    Guermonprez, P., Fayolle, C., Rojas, M. J., Rescigno, M., Ladant, D., & Leclerc, C. (2002). In vivo receptor-mediated delivery of a recombinant invasive bacterial toxoid to CD11c+CD8alpha-CD11bhigh dendritic cells. European Journal of Immunology, 32, 3071–081.PubMedCrossRefGoogle Scholar
  110. 110.
    Randolph, G. J., Angeli, V., & Swartz, M. A. (2005). Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nature Reviews Immunology, 5, 617–28.PubMedCrossRefGoogle Scholar
  111. 111.
    Sanchez-Sanchez, N., Riol-Blanco, L., & Rodriguez-Fernandez, J. L. (2006). The multiple personalities of the chemokine receptor CCR7 in dendritic cells. Journal of Immunology, 176, 5153–159.Google Scholar
  112. 112.
    Guermonprez, P., Valladeau, J., Zitvogel, L., Thery, C., & Amigorena, S. (2002). Antigen presentation and T cell stimulation by dendritic cells. Annual Review of Immunology, 20, 621–67.PubMedCrossRefGoogle Scholar
  113. 113.
    Reis e Sousa. (2006). Dendritic cells in a mature age. Nature Reviews Immunology, 6, 476–83.PubMedCrossRefGoogle Scholar
  114. 114.
    Sozzani, S. (2005). Dendritic cell trafficking: More than just chemokines. Cytokine & Growth Factor Reviews, 16, 581–92.CrossRefGoogle Scholar
  115. 115.
    Akashi, K., Traver, D., Miyamoto, T., & Weissman, I. L. (2000). A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature, 404, 193–97.PubMedCrossRefGoogle Scholar
  116. 116.
    Svensson, M., & Kaye, P. M. (2006). Stromal-cell regulation of dendritic-cell differentiation and function. Trends in Immunology, 27, 580–87.PubMedCrossRefGoogle Scholar
  117. 117.
    Perrot, I., Blanchard, C., Freymond, N., Isaac, S., Guibert, B., Pacheco, Y., et al. (2007). Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage. Journal of Immunology, 178, 2763–769.Google Scholar
  118. 118.
    Chang, C. C., Wright, A., & Punnonen, J. (2000). Monocyte-derived CD1a+ and CD1a- dendritic cell subsets differ in their cytokine production profiles, susceptibilities to transfection, and capacities to direct Th cell differentiation. Journal of Immunology, 165, 3584–591.Google Scholar
  119. 119.
    Parajuli, P., Mosley, R. L., Pisarev, V., Chavez, J., Ulrich, A., Varney, M., et al. (2001). Flt3 ligand and granulocyte-macrophage colony-stimulation factor preferentially expand and stimulate different dendritic cell and T cell subsets. Experimental Hematology, 29, 1185–193.PubMedCrossRefGoogle Scholar
  120. 120.
    Caux, C., Vanbervliet, B., Massacrier, C., zutter-Dambuyant, C., de Saint-Vis, B., Jacquet, C., et al. (1996). CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha. Journal of Experimental Medicine, 184, 695–06.PubMedCrossRefGoogle Scholar
  121. 121.
    Bender, A., Sapp, M., Schuler, G., Steinman, R. M., & Bhardwaj, N. (1996). Improved methods for the generation of dendritic cells from nonproliferating progenitors in human blood. Journal of Immunological Methods, 196, 121–35.PubMedCrossRefGoogle Scholar
  122. 122.
    Roy, K. C., Bandyopadhyay, G., Rakshit, S., Ray, M., & Bandyopadhyay, S. (2004). IL-4 alone without the involvement of GM-CSF transforms human peripheral blood monocytes to a CD1a(dim), CD83(+) myeloid dendritic cell subset. Journal of Cell Science, 117, 3435–445.PubMedCrossRefGoogle Scholar
  123. 123.
    Vremec, D., Lieschke, G. J., Dunn, A. R., Robb, L., Metcalf, D., & Shortman, K. (1997). The influence of granulocyte/macrophage colony-stimulating factor on dendritic cell levels in mouse lymphoid organs. European Journal of Immunology, 27, 40–4.PubMedCrossRefGoogle Scholar
  124. 124.
    McKenna, H. J., Stocking, K. L., Miller, R. E., Brasel, K., De Smedt, T., Maraskovsky, E., et al. (2000). Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood, 95, 3489–497.PubMedGoogle Scholar
  125. 125.
    Solheim, J. C., Reber, A. J., Ashour, A. E., Robinson, S., Futakuchi, M., Kurz, S. G., et al. (2007). Spleen but not tumor infiltration by dendritic and T cells is increased by intravenous adenovirus-Flt3 ligand injection. Cancer Gene Therapy.Google Scholar
  126. 126.
    Mora, J. R., Bono, M. R., Manjunath, N., Weninger, W., Cavanagh, L. L., Rosemblatt, M., et al. (2003). Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature, 424, 88–3.PubMedCrossRefGoogle Scholar
  127. 127.
    Shurin, M. R., Shurin, G. V., Lokshin, A., Yurkovetsky, Z. R., Gutkin, D. W., Chatta, G., et al. (2006). Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: Friends or enemies? Cancer and Metastasis Reviews, 25, 333–56.PubMedCrossRefGoogle Scholar
  128. 128.
    Shurin, M., & Gabrilovich, D. (2001). Regulation of dendritic cell system by tumor. Cancer Research, Therapy and Control, 11, 65–8.Google Scholar
  129. 129.
    Reichert, T. E., Scheuer, C., Day, R., Wagner, W., & Whiteside, T. L. (2001). The number of intratumoral dendritic cells and zeta-chain expression in T cells as prognostic and survival biomarkers in patients with oral carcinoma. Cancer, 91, 2136–147.PubMedCrossRefGoogle Scholar
  130. 130.
    Goldman, S. A., Baker, E., Weyant, R. J., Clarke, M. R., Myers, J. N., Lotze, M. T. (1998). Peritumoral CD1a-positive dendritic cells are associated with improved survival in patients with tongue carcinoma. Archives of Otolaryngology, Head & Neck Surgery, 124, 641–46.Google Scholar
  131. 131.
    Miyagawa, S., Soeda, J., Takagi, S., Miwa, S., Ichikawa, E., & Noike, T. (2004). Prognostic significance of mature dendritic cells and factors associated with their accumulation in metastatic liver tumors from colorectal cancer. Human Pathology, 35, 1392–396.PubMedCrossRefGoogle Scholar
  132. 132.
    Iwamoto, M., Shinohara, H., Miyamoto, A., Okuzawa, M., Mabuchi, H., Nohara, T., et al. (2003). Prognostic value of tumor-infiltrating dendritic cells expressing CD83 in human breast carcinomas. International Journal of Cancer, 104, 92–7.CrossRefGoogle Scholar
  133. 133.
    Shurin, G. V., Ferris, R., Tourkova, I. L., Perez, L., Lokshin, A., Balkir, L., et al. (2005). Loss of new chemokine CXCL14 in tumor tissue is associated with low infiltration by Dendritic Cells (DC), while restoration of human CXCL14 expression in tumor cells causes attraction of DC both in vitro and in vivo. Journal of Immunology, 174, 5490–498.Google Scholar
  134. 134.
    Melcher, A., Todryk, S., Bateman, A., Chong, H., Lemoine, N. R., & Vile, R. G. (1999). Adoptive transfer of immature dendritic cells with autologous or allogeneic tumor cells generates systemic antitumor immunity. Cancer Research, 59, 2802–805.PubMedGoogle Scholar
  135. 135.
    Tong, Y., Song, W., & Crystal, R. G. (2001). Combined intratumoral injection of bone marrow-derived dendritic cells and systemic chemotherapy to treat pre-existing murine tumors. Cancer Research, 61, 7530–535.PubMedGoogle Scholar
  136. 136.
    Sandel, M. H., Dadabayev, A. R., Menon, A. G., Morreau, H., Melief, C. J., Offringa, R., et al. (2005). Prognostic value of tumor-infiltrating dendritic cells in colorectal cancer: Role of maturation status and intratumoral localization. Clinical Cancer Research, 11, 2576–582.PubMedCrossRefGoogle Scholar
  137. 137.
    Bell, D., Chomarat, P., Broyles, D., Netto, G., Harb, G. M., Lebecque, S., et al. (1999). In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. Journal of Experimental Medicine, 190, 1417–426.PubMedCrossRefGoogle Scholar
  138. 138.
    Suzuki, A., Masuda, A., Nagata, H., Kameoka, S., Kikawada, Y., Yamakawa, M., et al. (2002). Mature dendritic cells make clusters with T cells in the invasive margin of colorectal carcinoma. Journal of Pathology, 196, 37–3.PubMedCrossRefGoogle Scholar
  139. 139.
    Pinder, S. E., Wencyk, P., Sibbering, D. M., Bell, J. A., Elston, C. W., Nicholson, R., et al. (1995). Assessment of the new proliferation marker MIB1 in breast carcinoma using image analysis: Associations with other prognostic factors and survival. British Journal of Cancer, 71, 146–49.PubMedGoogle Scholar
  140. 140.
    Coventry, B. J., & Morton, J. (2003). CD1a-positive infiltrating-dendritic cell density and 5-year survival from human breast cancer. British Journal of Cancer, 89, 533–38.PubMedCrossRefGoogle Scholar
  141. 141.
    Treilleux, I., Blay, J. Y., driss-Vermare, N., Ray-Coquard, I., Bachelot, T., Guastalla, J. P., et al. (2004). Dendritic cell infiltration and prognosis of early stage breast cancer. Clinical Cancer Research, 10, 7466–474.PubMedCrossRefGoogle Scholar
  142. 142.
    Hakim, A. (1979). Tumor-mediated immunsuppression is a chllenge in cancer treatment. Cancer Immunology and Immunotherapy, 7, 1–.Google Scholar
  143. 143.
    Gabrilovich, D. I., Chen, H. L., Girgis, K. R., Cunningham, H. T., Meny, G. M., Nadaf, S., et al. (1996). Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nature Medicine, 2, 1096–103.PubMedCrossRefGoogle Scholar
  144. 144.
    Wojtowicz-Praga, S. (1997). Reversal of tumor-induced immunosuppression: A new approach to cancer therapy. Journal of Immunotherapy, 20, 165–77.PubMedCrossRefGoogle Scholar
  145. 145.
    Shurin, M. R., Yurkovetsky, Z. R., Tourkova, I. L., Balkir, L., & Shurin, G. V. (2002). Inhibition of CD40 expression and CD40-mediated dendritic cell function by tumor-derived IL-10. International Journal of Cancer, 101, 61–8.CrossRefGoogle Scholar
  146. 146.
    Yanagimoto, H., Takai, S., Satoi, S., Toyokawa, H., Takahashi, K., Terakawa, N., et al. (2005). Impaired function of circulating dendritic cells in patients with pancreatic cancer. Clinical Immunology, 114, 52–0.PubMedCrossRefGoogle Scholar
  147. 147.
    Wojas, K., Tabarkiewicz, J., Jankiewicz, M., & Rolinski, J. (2004). Dendritic cells in peripheral blood of patients with breast and lung cancer—a pilot study. Folia Histochemica et Cytobiologica, 42, 45–8.PubMedGoogle Scholar
  148. 148.
    Della, P. M., Danova, M., Rigolin, G. M., Brugnatelli, S., Rovati, B., Tronconi, C., et al. (2005). Dendritic cells and vascular endothelial growth factor in colorectal cancer: Correlations with clinicobiological findings. Oncology, 68, 276–84.CrossRefGoogle Scholar
  149. 149.
    Vakkila, J., Thomson, A. W., Vettenranta, K., Sariola, H., & Saarinen-Pihkala, U. M. (2004). Dendritic cell subsets in childhood and in children with cancer: Relation to age and disease prognosis. Clinical and Experimental Immunology, 135, 455–61.PubMedCrossRefGoogle Scholar
  150. 150.
    Gabrilovich, D. (2004). Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nature Reviews Immunology, 4, 941–52.PubMedCrossRefGoogle Scholar
  151. 151.
    Preynat-Seauve, O., Schuler, P., Contassot, E., Beermann, F., Huard, B., & French, L. E. (2006). Tumor-infiltrating dendritic cells are potent antigen-presenting cells able to activate T cells and mediate tumor rejection. Journal of Immunology, 176, 61–7.Google Scholar
  152. 152.
    Gabrilovich, D. I., Bronte, V., Chen, S. H., Colombo, M. P., Ochoa, A., Ostrand-Rosenberg, S., et al. (2007). The terminology issue for myeloid-derived suppressor cells. Cancer Research, 67, 425.PubMedCrossRefGoogle Scholar
  153. 153.
    Bronte, V., Wang, M., Overwijk, W. W., Surman, D. R., Pericle, F., Rosenberg, S. A., et al. (1998). Apoptotic death of CD8+ T lymphocytes after immunization: Induction of a suppressive population of Mac-1+/Gr-1+ cells. Journal of Immunology, 161, 5313–320.Google Scholar
  154. 154.
    Leenen, P. J., de Bruijn, M. F., Voerman, J. S., Campbell, P. A., & van, E. W. (1994). Markers of mouse macrophage development detected by monoclonal antibodies. Journal of Immunological Methods, 174, 5–9.PubMedCrossRefGoogle Scholar
  155. 155.
    Gallina, G., Dolcetti, L., Serafini, P., De, S. C., Marigo, I., Colombo, M. P., et al. (2006). Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. Journal of Clinical Investigation, 116, 2777–790.PubMedCrossRefGoogle Scholar
  156. 156.
    Huang, B., Pan, P. Y., Li, Q., Sato, A. I., Levy, D. E., Bromberg, J., et al. (2006). Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Research, 66, 1123–131.PubMedCrossRefGoogle Scholar
  157. 157.
    Kusmartsev, S., & Gabrilovich, D. I. (2005). STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. Journal of Immunology, 174, 4880–891.Google Scholar
  158. 158.
    Mirza, N., Fishman, M., Fricke, I., Dunn, M., Neuger, A. M., Frost, T. J., et al. (2006). All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Research, 66, 9299–307.PubMedCrossRefGoogle Scholar
  159. 159.
    Parmiani, G., Castelli, C., Pilla, L., Santinami, M., Colombo, M. P., & Rivoltini, L. (2007). Opposite immune functions of GM-CSF administered as vaccine adjuvant in cancer patients. Annals of Oncology, 18, 226–32.PubMedCrossRefGoogle Scholar
  160. 160.
    Ochoa, A. C., Zea, A. H., Hernandez, C., & Rodriguez, P. C. (2007). Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clinical Cancer Research, 13, 721s–26s.PubMedCrossRefGoogle Scholar
  161. 161.
    Almand, B., Clark, J. I., Nikitina, E., van Beynen, J., English, N. R., Knight, S. C., et al. (2001). Increased production of immature myeloid cells in cancer patients: A mechanism of immunosuppression in cancer. Journal of Immunology, 166, 678–89.Google Scholar
  162. 162.
    Almand, B., Resser, J. R., Lindman, B., Nadaf, S., Clark, J. I., Kwon, E. D., et al. (2000). Clinical significance of defective dendritic cell differentiation in cancer. Clinical Cancer Research, 6, 1755–766.PubMedGoogle Scholar
  163. 163.
    Serafini, P., De Santo, C., Marigo, I., Cingarlini, S., Dolcetti, L., Gallina, G., et al. (2004). Derangement of immune responses by myeloid suppressor cells. Cancer Immunology and Immunotherapy, 53, 64–2.PubMedCrossRefGoogle Scholar
  164. 164.
    Baniyash, M. (2004). TCR zeta-chain downregulation: Curtailing an excessive inflammatory immune response. Nature Reviews Immunology, 4, 675–87.PubMedCrossRefGoogle Scholar
  165. 165.
    Strober, S. (1984). Natural suppressor (NS) cells, neonatal tolerance, and total lymphoid irradiation: Exploring obscure relationships. Annual Review of Immunology, 2, 219–37.PubMedCrossRefGoogle Scholar
  166. 166.
    Holda, J. H., Maier, T., & Claman, H. N. (1985). Murine graft-versus-host disease across minor barriers: Immunosuppressive aspects of natural suppressor cells. Immunological Reviews, 88, 87–05.PubMedCrossRefGoogle Scholar
  167. 167.
    Badger, A. M., King, A. G., Talmadge, J. E., Schwartz, D. A., Picker, D. H., Mirabelli, C. K., et al. (1990). Induction of non-specific suppressor cells in normal Lewis rats by a novel azaspirane SK&F 105685. Journal of Autoimmunity, 3, 485–00.PubMedCrossRefGoogle Scholar
  168. 168.
    Bronte, V., Apolloni, E., Cabrelle, A., Ronca, R., Serafini, P., Zamboni, P., et al. (2000). Identification of a CD11b(+)/Gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells. Blood, 96, 3838–846.PubMedGoogle Scholar
  169. 169.
    Serafini, P., Carbley, R., Noonan, K. A., Tan, G., Bronte, V., & Borrello, I. (2004). High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer Research, 64, 6337–343.PubMedCrossRefGoogle Scholar
  170. 170.
    Young, M. R., & Lathers, D. M. (1999). Myeloid progenitor cells mediate immune suppression in patients with head and neck cancers. International Journal of Immunopharmacology, 21, 241–52.PubMedCrossRefGoogle Scholar
  171. 171.
    Dranoff, G. (2003). GM-CSF-secreting melanoma vaccines. Oncogene, 22, 3188–192.PubMedCrossRefGoogle Scholar
  172. 172.
    Menetrier-Caux, C., Montmain, G., Dieu, M. C., Bain, C., Favrot, M. C., Caux, C., et al. (1998). Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: Role of interleukin-6 and macrophage colony-stimulating factor. Blood, 92, 4778–791.PubMedGoogle Scholar
  173. 173.
    Young, M. R., Wright, M. A., & Young, M. E. (1991). Antibodies to colony-stimulating factors block Lewis lung carcinoma cell stimulation of immune-suppressive bone marrow cells. Cancer Immunology and Immunotherapy, 33, 146–52.PubMedCrossRefGoogle Scholar
  174. 174.
    Ohm, J. E., & Carbone, D. P. (2001). VEGF as a mediator of tumor-associated immunodeficiency. Immunologic Research, 23, 263–72.PubMedCrossRefGoogle Scholar
  175. 175.
    Gabrilovich, D., Ishida, T., Oyama, T., Ran, S., Kravtsov, V., Nadaf, S., et al. (1998). Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood, 92, 4150–166.PubMedGoogle Scholar
  176. 176.
    Ellis, L. M., Takahashi, Y., Liu, W., & Shaheen, R. M. (2000). Vascular endothelial growth factor in human colon cancer: Biology and therapeutic implications. Oncologist, 5(Suppl 1), 11–5.PubMedCrossRefGoogle Scholar
  177. 177.
    Toi, M., Kondo, S., Suzuki, H., Yamamoto, Y., Inada, K., Imazawa, T., et al. (1996). Quantitative analysis of vascular endothelial growth factor in primary breast cancer. Cancer, 77, 1101–106.PubMedCrossRefGoogle Scholar
  178. 178.
    Melani, C., Chiodoni, C., Forni, G., & Colombo, M. P. (2003). Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity. Blood, 102, 2138–145.PubMedCrossRefGoogle Scholar
  179. 179.
    Saito, H., Tsujitani, S., Ikeguchi, M., Maeta, M., & Kaibara, N. (1998). Relationship between the expression of vascular endothelial growth factor and the density of dendritic cells in gastric adenocarcinoma tissue. British Journal of Cancer, 78, 1573–577.PubMedGoogle Scholar
  180. 180.
    Gabrilovich, D. I., Ishida, T., Nadaf, S., Ohm, J. E., & Carbone, D. P. (1999). Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clinical Cancer Research, 5, 2963–970.PubMedGoogle Scholar
  181. 181.
    Pereg, D., & Lishner, M. (2005). Non-steroidal anti-inflammatory drugs for the prevention and treatment of cancer. Journal of Internal Medicine, 258, 115–23.PubMedCrossRefGoogle Scholar
  182. 182.
    Dannenberg, A. J., Altorki, N. K., Boyle, J. O., Dang, C., Howe, L. R., Weksler, B. B., et al. (2001). Cyclo-oxygenase 2: A pharmacological target for the prevention of cancer. Lancet Oncology, 2, 544–51.PubMedCrossRefGoogle Scholar
  183. 183.
    Rodriguez, P. C., Hernandez, C. P., Quiceno, D., Dubinett, S. M., Zabaleta, J., Ochoa, J. B., et al. (2005). Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. Journal of Experimental Medicine, 202, 931–39.PubMedCrossRefGoogle Scholar
  184. 184.
    Stolina, M., Sharma, S., Lin, Y., Dohadwala, M., Gardner, B., Luo, J., et al. (2000). Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. Journal of Immunology, 164, 361–70.Google Scholar
  185. 185.
    Talmadge, J. E., Hood, K. C., Zobel, L. C., Shafer, L. R., Coles, M., & Toth, B. (2007). Chemoprevention by cyclooxygenase-2 inhibition reduces immature myeloid suppressor cell expansion. International Immunopharmacology, 7, 140–51.PubMedCrossRefGoogle Scholar
  186. 186.
    Sharma, S., Zhu, L., Yang, S. C., Zhang, L., Lin, J., Hillinger, S., et al. (2005). Cyclooxygenase 2 inhibition promotes IFN-{gamma}-dependent enhancement of antitumor responses. Journal of Immunology, 175, 813–19.Google Scholar
  187. 187.
    Haas, A. R., Sun, J., Vachani, A., Wallace, A. F., Silverberg, M., Kapoor, V., et al. (2006). Cycloxygenase-2 inhibition augments the efficacy of a cancer vaccine. Clinical Cancer Research, 12, 214–22.PubMedCrossRefGoogle Scholar
  188. 188.
    Angulo, I., Rullas, J., Campillo, J. A., Obregon, E., Heath, A., Howard, M., et al. (2000). Early myeloid cells are high producers of nitric oxide upon CD40 plus IFN-gamma stimulation through a mechanism dependent on endogenous TNF-alpha and IL-1alpha. European Journal of Immunology, 30, 1263–271.PubMedCrossRefGoogle Scholar
  189. 189.
    Munder, M., Eichmann, K., Moran, J. M., Centeno, F., Soler, G., & Modolell, M. (1999). Th1/Th2-regulated expression of arginase isoforms in murine macrophages and dendritic cells. Journal of Immunology, 163, 3771–777.Google Scholar
  190. 190.
    Boutard, V., Havouis, R., Fouqueray, B., Philippe, C., Moulinoux, J. P., & Baud, L. (1995). Transforming growth factor-beta stimulates arginase activity in macrophages. Implications for the regulation of macrophage cytotoxicity. Journal of Immunology, 155, 2077–084.Google Scholar
  191. 191.
    Jost, M. M., Ninci, E., Meder, B., Kempf, C., Van, R. N., Hua, J., et al. (2003). Divergent effects of GM-CSF and TGFbeta1 on bone marrow-derived macrophage arginase-1 activity, MCP-1 expression, and matrix metalloproteinase-12: A potential role during arteriogenesis. FASEB Journal, 17, 2281–283.PubMedGoogle Scholar
  192. 192.
    Duval, D. L., Miller, D. R., Collier, J., & Billings, R. E. (1996). Characterization of hepatic nitric oxide synthase: Identification as the cytokine-inducible form primarily regulated by oxidants. Molecular Pharmacology, 50, 277–84.PubMedGoogle Scholar
  193. 193.
    Bronte, V., Serafini, P., De Santo, C., Marigo, I., Tosello, V., Mazzoni, A., et al. (2003). IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. Journal of Immunology, 170, 270–78.Google Scholar
  194. 194.
    De Santo, C., Serafini, P., Marigo, I., Dolcetti, L., Bolla, M., Del, S. P., et al. (2005). Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proceedings of the National Academy of Sciences of the United States of America, 102, 4185–190.PubMedCrossRefGoogle Scholar
  195. 195.
    Radi, R. (2004). Nitric oxide, oxidants, and protein tyrosine nitration. Proceedings of the National Academy of Sciences of the United States of America, 101, 4003–008.PubMedCrossRefGoogle Scholar
  196. 196.
    Aulak, K. S., Miyagi, M., Yan, L., West, K. A., Massillon, D., Crabb, J. W., et al. (2001). Proteomic method identifies proteins nitrated in vivo during inflammatory challenge. Proceedings of the National Academy of Sciences of the United States of America, 98, 12056–2061.PubMedCrossRefGoogle Scholar
  197. 197.
    Reth, M. (2002). Hydrogen peroxide as second messenger in lymphocyte activation. Nature Immunology, 3, 1129–134.PubMedCrossRefGoogle Scholar
  198. 198.
    Kono, K., Salazar-Onfray, F., Petersson, M., Hansson, J., Masucci, G., Wasserman, K., et al. (1996). Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal-transducing zeta molecules and inhibits tumor-specific T cell-and natural killer cell-mediated cytotoxicity. European Journal of Immunology, 26, 1308–313.PubMedCrossRefGoogle Scholar
  199. 199.
    Corsi, M. M., Maes, H. H., Wasserman, K., Fulgenzi, A., Gaja, G., & Ferrero, M. E. (1998). Protection by L-2-oxothiazolidine-4-carboxylic acid of hydrogen peroxide-induced CD3zeta and CD16zeta chain down-regulation in human peripheral blood lymphocytes and lymphokine-activated killer cells. Biochemical Pharmacology, 56, 657–62.PubMedCrossRefGoogle Scholar
  200. 200.
    Hildeman, D. A., Mitchell, T., Aronow, B., Wojciechowski, S., Kappler, J., & Marrack, P. (2003). Control of Bcl-2 expression by reactive oxygen species. Proceedings of the National Academy of Sciences of the United States of America, 100, 15035–5040.PubMedCrossRefGoogle Scholar
  201. 201.
    Seung, L. P., Rowley, D. A., Dubey, P., & Schreiber, H. (1995). Synergy between T-cell immunity and inhibition of paracrine stimulation causes tumor rejection. Proceedings of the National Academy of Sciences of the United States of America, 92, 6254–258.PubMedCrossRefGoogle Scholar
  202. 202.
    Kusmartsev, S., Cheng, F., Yu, B., Nefedova, Y., Sotomayor, E., Lush, R., et al. (2003). All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Research, 63, 4441–449.PubMedGoogle Scholar
  203. 203.
    Pak, A. S., Ip, G., Wright, M. A., & Young, M. R. (1994). Treating tumor-bearing mice with low-dose gamma-interferon plus tumor necrosis factor alpha to diminish immune suppressive granulocyte-macrophage progenitor cells increases responsiveness in interleukin-2 immunotherapy. Cancer Research, 55, 885–90.Google Scholar
  204. 204.
    Sinha, P., Clements, V. K., Fulton, A., & Ostrand-Rosenberg, S. (2007). Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Research, 67, 4507–513.PubMedCrossRefGoogle Scholar
  205. 205.
    Young, M. R., Lozano, Y., Ihm, J., Wright, M. A., & Prechel, M. M. (1996). Vitamin D3 treatment of tumor bearers can stimulate immune competence and reduce tumor growth when treatment coincides with a heightened presence of natural suppressor cells. Cancer Letters, 104, 153–61.PubMedCrossRefGoogle Scholar
  206. 206.
    Lathers, D. M., Clark, J. I., Achille, N. J., & Young, M. R. (2004). Phase 1B study to improve immune responses in head and neck cancer patients using escalating doses of 25-hydroxyvitamin D3. Cancer Immunology and Immunotherapy, 53, 422–30.PubMedCrossRefGoogle Scholar
  207. 207.
    Wallace, J. L., Ignarro, L. J., & Fiorucci, S. (2002). Potential cardioprotective actions of no-releasing aspirin. Nature Reviews Drug Discovery, 1, 375–82.PubMedCrossRefGoogle Scholar
  208. 208.
    Bronte, V., Serafini, P., Mazzoni, A., Segal, D. M., & Zanovello, P. (2003). L-arginine metabolism in myeloid cells controls T-lymphocyte functions. Trends in Immunology, 24, 302–06.PubMedCrossRefGoogle Scholar
  209. 209.
    Finke, J. (2007). Promotion of a type-1 cell response in metastatic RCC patients by SU11248: Modulation of a T-reg population. Molecular Targets in Cancer Therapy Conference.Google Scholar
  210. 210.
    Huang, B., Lei, Z., Zhao, J., Gong, W., Liu, J., Chen, Z., et al. (2007). CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Letters, 252, 86–2.PubMedCrossRefGoogle Scholar
  211. 211.
    Belli, F., Testori, A., Rivoltini, L., Maio, M., Andreola, G., Sertoli, M. R., et al. (2002). Vaccination of metastatic melanoma patients with autologous tumor-derived heat shock protein gp96-peptide complexes: Clinical and immunologic findings. Journal of Clinical Oncology, 20, 4169–180.PubMedCrossRefGoogle Scholar
  212. 212.
    Gervois, N., Guilloux, Y., Diez, E., & Jotereau, F. (1996). Suboptimal activation of melanoma infiltrating lymphocytes (TIL) due to low avidity of TCR/MHC-tumor peptide interactions. Journal of Experimental Medicine, 183, 2403–407.PubMedCrossRefGoogle Scholar
  213. 213.
    Clark, W. H. Jr., Elder, D. E., Guerry, D., Braitman, L. E., Trock, B. J., Schultz, D., et al. (1989). Model predicting survival in stage I melanoma based on tumor progression. Journal of the National Cancer Institute, 81, 1893–904.PubMedCrossRefGoogle Scholar
  214. 214.
    Zhang, L., Conejo-Garcia, J. R., Katsaros, D., Gimotty, P. A., Massobrio, M., Regnani, G., et al. (2003). Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. New England Journal of Medicine, 348, 203–13.PubMedCrossRefGoogle Scholar
  215. 215.
    Curiel, T. J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., et al. (2004). Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Medicine, 10, 942–49.PubMedCrossRefGoogle Scholar
  216. 216.
    Ohtani, H., Naito, Y., Saito, K., & Nagura, H. (1997). Expression of costimulatory molecules B7-1 and B7-2 by macrophages along invasive margin of colon cancer: A possible antitumor immunity? Laboratory Investigation, 77, 231–41.PubMedGoogle Scholar
  217. 217.
    Menon, A. G., Janssen-van Rhijn, C. M., Morreau, H., Putter, H., Tollenaar, R. A., van d, V., et al. (2004). Immune system and prognosis in colorectal cancer: A detailed immunohistochemical analysis. Laboratory Investigation, 84, 493–01.PubMedCrossRefGoogle Scholar
  218. 218.
    Naito, Y., Saito, K., Shiiba, K., Ohuchi, A., Saigenji, K., Nagura, H., et al. (1998). CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Research, 58, 3491–494.PubMedGoogle Scholar
  219. 219.
    Menon, A. G., Morreau, H., Tollenaar, R. A., Alphenaar, E., Van, P. M., Putter, H., et al. (2002). Down-regulation of HLA-A expression correlates with a better prognosis in colorectal cancer patients. Laboratory Investigation, 82, 1725–733.PubMedGoogle Scholar
  220. 220.
    Zou, W. (2005). Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nature Reviews Cancer, 5, 263–74.PubMedCrossRefGoogle Scholar
  221. 221.
    Piersma, S. J., Jordanova, E. S., van Poelgeest, M. I., Kwappenberg, K. M., van der Hulst, J. M., Drijfhout, J. W., et al. (2007). High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer. Cancer Research, 67, 354–61.PubMedCrossRefGoogle Scholar
  222. 222.
    Nakano, O., Sato, M., Naito, Y., Suzuki, K., Orikasa, S., Aizawa, M., et al. (2001). Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: Clinicopathologic demonstration of antitumor immunity. Cancer Research, 61, 5132–136.PubMedGoogle Scholar
  223. 223.
    Yu, P., Lee, Y., Liu, W., Krausz, T., Chong, A., Schreiber, H., et al. (2005). Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. Journal of Experimental Medicine, 201, 779–91.PubMedCrossRefGoogle Scholar
  224. 224.
    Turk, M. J., Guevara-Patino, J. A., Rizzuto, G. A., Engelhorn, M. E., Sakaguchi, S., & Houghton, A. N. (2004). Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. Journal of Experimental Medicine, 200, 771–82.PubMedCrossRefGoogle Scholar
  225. 225.
    Shimizu, J., Yamazaki, S., & Sakaguchi, S. (1999). Induction of tumor immunity by removing CD25+CD4+ T cells: A common basis between tumor immunity and autoimmunity. Journal of Immunology, 163, 5211–218.Google Scholar
  226. 226.
    Onizuka, S., Tawara, I., Shimizu, J., Sakaguchi, S., Fujita, T., & Nakayama, E. (1999). Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Research, 59, 3128–133.PubMedGoogle Scholar
  227. 227.
    Ohtani, H. (2007). Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immunity, 7, 4PubMedGoogle Scholar
  228. 228.
    Kolbeck, P. C., Kaveggia, F. F., Johansson, S. L., Grune, M. T., & Taylor, R. J. (1992). The relationships among tumor-infiltrating lymphocytes, histopathologic findings, and long-term clinical follow-up in renal cell carcinoma. Modern Pathology, 5, 420–25.PubMedGoogle Scholar
  229. 229.
    Bromwich, E. J., McArdle, P. A., Canna, K., McMillan, D. C., McNicol, A. M., Brown, M., et al. (2003). The relationship between T-lymphocyte infiltration, stage, tumour grade and survival in patients undergoing curative surgery for renal cell cancer. British Journal of Cancer, 89, 1906–908.PubMedCrossRefGoogle Scholar
  230. 230.
    Siddiqui, S. A., Frigola, X., Bonne-Annee, S., Mercader, M., Kuntz, S. M., Krambeck, A. E., et al. (2007). Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma. Clinical Cancer Research, 13, 2075–081.PubMedCrossRefGoogle Scholar
  231. 231.
    Thorn, M., Ponten, F., Bergstrom, R., Sparen, P., & Adami, H. O. (1994). Clinical and histopathologic predictors of survival in patients with malignant melanoma: A population-based study in Sweden. Journal of the National Cancer Institute, 86, 761–69.PubMedCrossRefGoogle Scholar
  232. 232.
    Gershenwald, J. E., Thompson, W., Mansfield, P. F., Lee, J. E., Colome, M. I., Tseng, C. H., et al. (1999). Multi-institutional melanoma lymphatic mapping experience: The prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. Journal of Clinical Oncology, 17, 976–83.PubMedGoogle Scholar
  233. 233.
    Elder, D. E., Gimotty, P. A., & Guerry, D. (2005). Cutaneous melanoma: Estimating survival and recurrence risk based on histopathologic features. Dermatologic Therapy, 18, 369–85.PubMedCrossRefGoogle Scholar
  234. 234.
    Reed, J. A., McNutt, N. S., Prieto, V. G., & Albino, A. P. (1994). Expression of transforming growth factor-beta 2 in malignant melanoma correlates with the depth of tumor invasion. Implications for tumor progression. American Journal of Pathology, 145, 97–04.PubMedGoogle Scholar
  235. 235.
    Badoual, C., Hans, S., Rodriguez, J., Peyrard, S., Klein, C., Agueznay, N. H., et al. (2006). Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clinical Cancer Research, 12, 465–72.PubMedCrossRefGoogle Scholar
  236. 236.
    Pages, F., Berger, A., Camus, M., Sanchez-Cabo, F., Costes, A., Molidor, R., et al. (2005). Effector memory T cells, early metastasis, and survival in colorectal cancer. New England Journal of Medicine, 353, 2654–666.PubMedCrossRefGoogle Scholar
  237. 237.
    Taylor, R. C., Patel, A., Panageas, K. S., Busam, K. J., & Brady, M. S. (2007). Tumor-infiltrating lymphocytes predict sentinel lymph node positivity in patients with cutaneous melanoma. Journal of Clinical Oncology, 25, 869–75.PubMedCrossRefGoogle Scholar
  238. 238.
    Balch, C. M., Soong, S. J., Gershenwald, J. E., Thompson, J. F., Reintgen, D. S., Cascinelli, N., et al. (2001). Prognostic factors analysis of 17,600 melanoma patients: Validation of the American Joint Committee on Cancer melanoma staging system. Journal of Clinical Oncology, 19, 3622–634.PubMedGoogle Scholar
  239. 239.
    Kruper, L., Botbyl, B., Czerniecki, B., Elder, D., Fraker, D., Ming, M., et al. (2005). Predicting sentinel lymph node status in stage I/II melanoma. Journal of Clinical Oncology, ASCO Meeting Abstracts 23, 7501.Google Scholar
  240. 240.
    Chen, Q., Wang, W. C., & Evans, S. S. (2003). Tumor microvasculature as a barrier to antitumor immunity. Cancer Immunology and Immunotherapy, 52, 670–79.PubMedCrossRefGoogle Scholar
  241. 241.
    Inoshima, N., Nakanishi, Y., Minami, T., Izumi, M., Takayama, K., Yoshino, I., et al. (2002). The influence of dendritic cell infiltration and vascular endothelial growth factor expression on the prognosis of non-small cell lung cancer. Clinical Cancer Research, 8, 3480–486.PubMedGoogle Scholar
  242. 242.
    Dvorak, H. F. (1986). Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. New England Journal of Medicine, 315, 1650–659.PubMedCrossRefGoogle Scholar
  243. 243.
    Sica, A., Schioppa, T., Mantovani, A., & Allavena, P. (2006). Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: Potential targets of anti-cancer therapy. European Journal of Cancer, 42, 717–27.PubMedCrossRefGoogle Scholar
  244. 244.
    Ben-Baruch, A. (2003). Host microenvironment in breast cancer development: Inflammatory cells, cytokines and chemokines in breast cancer progression: Reciprocal tumor-microenvironment interactions. Breast Cancer Research, 5, 31–6.PubMedCrossRefGoogle Scholar
  245. 245.
    Malmberg, K. J. (2004). Effective immunotherapy against cancer: A question of overcoming immune suppression and immune escape? Cancer Immunology and Immunotherapy, 53, 879–92.PubMedGoogle Scholar
  246. 246.
    Rodriguez, P. C., Quiceno, D. G., Zabaleta, J., Ortiz, B., Zea, A. H., Piazuelo, M. B., et al. (2004). Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Research, 64, 5839–849.PubMedCrossRefGoogle Scholar
  247. 247.
    Chang, C. I., Liao, J. C., & Kuo, L. (2001). Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity. Cancer Research, 61, 1100–106.PubMedGoogle Scholar
  248. 248.
    Gualandris, A., Rusnati, M., Belleri, M., Nelli, E. E., Bastaki, M., Molinari-Tosatti, M. P., et al. (1996). Basic fibroblast growth factor overexpression in endothelial cells: An autocrine mechanism for angiogenesis and angioproliferative diseases. Cell Growth & Differentiation, 7, 147–60.Google Scholar
  249. 249.
    Scarpino, S., Stoppacciaro, A., Ballerini, F., Marchesi, M., Prat, M., Stella, M. C., et al. (2000). Papillary carcinoma of the thyroid: Hepatocyte growth factor (HGF) stimulates tumor cells to release chemokines active in recruiting dendritic cells. American Journal of Pathology, 156, 831–37.PubMedGoogle Scholar
  250. 250.
    Monti, P., Leone, B. E., Marchesi, F., Balzano, G., Zerbi, A., Scaltrini, F., et al. (2003). The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: Regulation of expression and potential mechanisms of antimalignant activity. Cancer Research, 63, 7451–461.PubMedGoogle Scholar
  251. 251.
    Saji, H., Koike, M., Yamori, T., Saji, S., Seiki, M., Matsushima, K., et al. (2001). Significant correlation of monocyte chemoattractant protein-1 expression with neovascularization and progression of breast carcinoma. Cancer, 92, 1085–091.PubMedCrossRefGoogle Scholar
  252. 252.
    Mantovani, A., Allavena, P., Sozzani, S., Vecchi, A., Locati, M., & Sica, A. (2004). Chemokines in the recruitment and shaping of the leukocyte infiltrate of tumors. Seminars in Cancer Biology, 14, 155–60.PubMedCrossRefGoogle Scholar
  253. 253.
    Moran, C. J., Arenberg, D. A., Huang, C. C., Giordano, T. J., Thomas, D. G., Misek, D. E., et al. (2002). RANTES expression is a predictor of survival in stage I lung adenocarcinoma. Clinical Cancer Research, 8, 3803–812.PubMedGoogle Scholar
  254. 254.
    Robinson, S. C., Scott, K. A., Wilson, J. L., Thompson, R. G., Proudfoot, A. E., & Balkwill, F. R. (2003). A chemokine receptor antagonist inhibits experimental breast tumor growth. Cancer Research, 63, 8360–365.PubMedGoogle Scholar
  255. 255.
    Thomachot, M. C., driss-Vermare, N., Massacrier, C., Biota, C., Treilleux, I., Goddard, S., et al. (2004). Breast carcinoma cells promote the differentiation of CD34+ progenitors towards 2 different subpopulations of dendritic cells with CD1a(high)CD86(-)Langerin- and CD1a(+)CD86(+)Langerin+ phenotypes. International Journal of Cancer, 110, 710–20.CrossRefGoogle Scholar
  256. 256.
    Curiel, T. J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., et al. (2004). Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Medicine, 10, 942–49.PubMedCrossRefGoogle Scholar
  257. 257.
    Singh, S., Singh, U. P., Stiles, J. K., Grizzle, W. E., & Lillard, J. W. Jr. (2004). Expression and functional role of CCR9 in prostate cancer cell migration and invasion. Clinical Cancer Research, 10, 8743–750.PubMedCrossRefGoogle Scholar
  258. 258.
    Gallo, O., Masini, E., Bianchi, B., Bruschini, L., Paglierani, M., & Franchi, A. (2002). Prognostic significance of cyclooxygenase-2 pathway and angiogenesis in head and neck squamous cell carcinoma. Human Pathology, 33, 708–14.PubMedCrossRefGoogle Scholar
  259. 259.
    Tsujii, M., Kawano, S., & DuBois, R. N. (1997). Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proceedings of the National Academy of Sciences of the United States of America, 94, 3336–340.PubMedCrossRefGoogle Scholar
  260. 260.
    Tang, T. C., Poon, R. T., Lau, C. P., Xie, D., & Fan, S. T. (2005). Tumor cyclooxygenase-2 levels correlate with tumor invasiveness in human hepatocellular carcinoma. World Journal of Gastroenterology, 11, 1896–902.PubMedGoogle Scholar
  261. 261.
    Dhawan, P., & Richmond, A. (2002). Role of CXCL1 in tumorigenesis of melanoma. Journal of Leukocyte Biology, 72, 9–8.PubMedGoogle Scholar
  262. 262.
    Haghnegahdar, H., Du, J., Wang, D., Strieter, R. M., Burdick, M. D., Nanney, L. B., et al. (2000). The tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma. Journal of Leukocyte Biology, 67, 53–2.PubMedGoogle Scholar
  263. 263.
    Van, C. E., Van, A. I., Wuyts, A., Vercauteren, R., Devos, R., De Wolf-Peeters, C., et al. (2001). Tumor angiogenesis induced by granulocyte chemotactic protein-2 as a countercurrent principle. American Journal of Pathology, 159, 1405–414.Google Scholar
  264. 264.
    Belperio, J. A., Keane, M. P., Arenberg, D. A., Addison, C. L., Ehlert, J. E., Burdick, M. D., et al. (2000). CXC chemokines in angiogenesis. Journal of Leukocyte Biology, 68, 1–.PubMedGoogle Scholar
  265. 265.
    Lin, Y., Huang, R., Chen, L., Li, S., Shi, Q., Jordan, C., et al. (2004). Identification of interleukin-8 as estrogen receptor-regulated factor involved in breast cancer invasion and angiogenesis by protein arrays. International Journal of Cancer, 109, 507–15.CrossRefGoogle Scholar
  266. 266.
    Singh, R. K., Gutman, M., Radinsky, R., Bucana, C. D., & Fidler, I. J. (1994). Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Research, 54, 3242–247.PubMedGoogle Scholar
  267. 267.
    Luster, A. D., & Leder, P. (1993). IP-10, a -C-X-C- chemokine, elicits a potent thymus-dependent antitumor response in vivo. Journal of Experimental Medicine, 178, 1057–065.PubMedCrossRefGoogle Scholar
  268. 268.
    Sun, H., Kundu, N., Dorsey, R., Jackson, M. J., & Fulton, A. M. (2001). Expression of the chemokines IP-10 and mig in IL-10 transduced tumors. Journal of Immunotherapy, 24, 138–43.CrossRefGoogle Scholar
  269. 269.
    Vanbervliet, B., driss-Vermare, N., Massacrier, C., Homey, B., de Bouteiller, O., Briere, F., et al. (2003). The inducible CXCR3 ligands control plasmacytoid dendritic cell responsiveness to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12. Journal of Experimental Medicine, 198, 823–30.PubMedCrossRefGoogle Scholar
  270. 270.
    Dorsey, R., Kundu, N., Yang, Q., Tannenbaum, C. S., Sun, H., Hamilton, T. A., et al. (2002). Immunotherapy with interleukin-10 depends on the CXC chemokines inducible protein-10 and monokine induced by IFN-gamma. Cancer Research, 62, 2606–610.PubMedGoogle Scholar
  271. 271.
    Balkwill, F. (2004). Cancer and the chemokine network. Nature Reviews Cancer, 4, 540–50.PubMedCrossRefGoogle Scholar
  272. 272.
    Singh, S., Singh, U. P., Grizzle, W. E., & Lillard, J. W. Jr. (2004). CXCL12’CXCR4 interactions modulate prostate cancer cell migration, metalloproteinase expression and invasion. Laboratory Investigation, 84, 1666–676.PubMedCrossRefGoogle Scholar
  273. 273.
    Herbst, R. S. (2004). Review of epidermal growth factor receptor biology. International Journal of Radiation Oncology, Biology, Physics, 59, 21–6.PubMedGoogle Scholar
  274. 274.
    Lamb, D. J., Modjtahedi, H., Plant, N. J., & Ferns, G. A. (2004). EGF mediates monocyte chemotaxis and macrophage proliferation and EGF receptor is expressed in atherosclerotic plaques. Atherosclerosis, 176, 21–6.PubMedCrossRefGoogle Scholar
  275. 275.
    Maraskovsky, E., Brasel, K., Teepe, M., Roux, E. R., Lyman, S. D., Shortman, K., et al. (1996). Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: Multiple dendritic cell subpopulations identified. Journal of Experimental Medicine, 184, 1953–962.PubMedCrossRefGoogle Scholar
  276. 276.
    Parajuli, P., Mosley, R. L., Pisarev, V., Chavez, J., Ulrich, A., Varney, M., et al. (2001). Flt3 ligand and granulocyte-macrophage colony-stimulating factor preferentially expand and stimulate different dendritic and T-cell subsets. Experimental Hematology, 29, 1185–193.PubMedCrossRefGoogle Scholar
  277. 277.
    Morris, E. S., MacDonald, K. P., Rowe, V., Johnson, D. H., Banovic, T., Clouston, A. D., et al. (2004). Donor treatment with pegylated G-CSF augments the generation of IL-10-producing regulatory T cells and promotes transplantation tolerance. Blood, 103, 3573–581.PubMedCrossRefGoogle Scholar
  278. 278.
    Okazaki, T., Ebihara, S., Asada, M., Kanda, A., Sasaki, H., & Yamaya, M. (2006). Granulocyte colony-stimulating factor promotes tumor angiogenesis via increasing circulating endothelial progenitor cells and Gr1+CD11b+ cells in cancer animal models. International Immunology, 18, 1–.PubMedCrossRefGoogle Scholar
  279. 279.
    Wislez, M., Rabbe, N., Marchal, J., Milleron, B., Crestani, B., Mayaud, C., et al. (2003). Hepatocyte growth factor production by neutrophils infiltrating bronchioloalveolar subtype pulmonary adenocarcinoma: Role in tumor progression and death. Cancer Research, 63, 1405–412.PubMedGoogle Scholar
  280. 280.
    Okunishi, K., Dohi, M., Nakagome, K., Tanaka, R., Mizuno, S., Matsumoto, K., et al. (2005). A novel role of hepatocyte growth factor as an immune regulator through suppressing dendritic cell function. Journal of Immunology, 175, 4745–753.Google Scholar
  281. 281.
    Uyttenhove, C., Pilotte, L., Theate, I., Stroobant, V., Colau, D., Parmentier, N., et al. (2003). Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nature Medicine, 9, 1269–274.PubMedCrossRefGoogle Scholar
  282. 282.
    Hwu, P., Du, M. X., Lapointe, R., Do, M., Taylor, M. W., & Young, H. A. (2000). Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. Journal of Immunology, 164, 3596–599.Google Scholar
  283. 283.
    Brandacher, G., Perathoner, A., Ladurner, R., Schneeberger, S., Obrist, P., Winkler, C., et al. (2006). Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: Effect on tumor-infiltrating T cells. Clinical Cancer Research, 12, 1144–151.PubMedCrossRefGoogle Scholar
  284. 284.
    Iizasa, H., Yoneyama, H., Mukaida, N., Katakoka, Y., Naito, M., Yoshida, N., et al. (2005). Exacerbation of granuloma formation in IL-1 receptor antagonist-deficient mice with impaired dendritic cell maturation associated with Th2 cytokine production. Journal of Immunology, 174, 3273–280.Google Scholar
  285. 285.
    Wesa, A., & Galy, A. (2002). Increased production of pro-inflammatory cytokines and enhanced T cell responses after activation of human dendritic cells with IL-1 and CD40 ligand. BMC Immunology, 3, 14.PubMedCrossRefGoogle Scholar
  286. 286.
    Song, X., Voronov, E., Dvorkin, T., Fima, E., Cagnano, E., Benharroch, D., et al. (2003). Differential effects of IL-1 alpha and IL-1 beta on tumorigenicity patterns and invasiveness. Journal of Immunology, 171, 6448–456.Google Scholar
  287. 287.
    He, Y. G., Mayhew, E., Mellon, J., & Niederkorn, J. Y. (2004). Expression and possible function of IL-2 and IL-15 receptors on human uveal melanoma cells. Investigative Ophthalmology & Visual Science, 45, 4240–246.CrossRefGoogle Scholar
  288. 288.
    Ratta, M., Fagnoni, F., Curti, A., Vescovini, R., Sansoni, P., Oliviero, B., et al. (2002). Dendritic cells are functionally defective in multiple myeloma: The role of interleukin-6. Blood, 100, 230–37.PubMedCrossRefGoogle Scholar
  289. 289.
    Tartour, E., Fossiez, F., Joyeux, I., Galinha, A., Gey, A., Claret, E., et al. (1999). Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Research, 59, 3698–704.PubMedGoogle Scholar
  290. 290.
    Guise, T. A., Kozlow, W. M., Heras-Herzig, A., Padalecki, S. S., Yin, J. J., & Chirgwin, J. M. (2005). Molecular mechanisms of breast cancer metastases to bone. Clinical Breast Cancer, 5(Suppl), S46’S53.PubMedCrossRefGoogle Scholar
  291. 291.
    Feijoo, E., Alfaro, C., Mazzolini, G., Serra, P., Penuelas, I., Arina, A., et al. (2005). Dendritic cells delivered inside human carcinomas are sequestered by interleukin-8. International Journal of Cancer, 116, 275–81.CrossRefGoogle Scholar
  292. 292.
    Yue, F. Y., Dummer, R., Geertsen, R., Hofbauer, G., Laine, E., Manolio, S., et al. (1997). Interleukin-10 is a growth factor for human melanoma cells and down-regulates HLA class-I, HLA class-II and ICAM-1 molecules. International Journal of Cancer, 71, 630–37.CrossRefGoogle Scholar
  293. 293.
    Sharma, S., Stolina, M., Lin, Y., Gardner, B., Miller, P. W., Kronenberg, M., et al. (1999). T cell-derived IL-10 promotes lung cancer growth by suppressing both T cell and APC function. Journal of Immunology, 163, 5020–028.Google Scholar
  294. 294.
    Curiel, T. J., Wei, S., Dong, H., Alvarez, X., Cheng, P., Mottram, P., et al. (2003). Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nature Medicine, 9, 562–67.PubMedCrossRefGoogle Scholar
  295. 295.
    Sgadari, C., Angiolillo, A. L., & Tosato, G. (1996). Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10. Blood, 87, 3877–882.PubMedGoogle Scholar
  296. 296.
    Strieter, R. M., Polverini, P. J., Kunkel, S. L., Arenberg, D. A., Burdick, M. D., Kasper, J., et al. (1995). The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. Journal of Biological Chemistry, 270, 27348–7357.PubMedCrossRefGoogle Scholar
  297. 297.
    Minty, A., Chalon, P., Derocq, J. M., Dumont, X., Guillemot, J. C., Kaghad, M., et al. (1993). Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature, 362, 248–50.PubMedCrossRefGoogle Scholar
  298. 298.
    Kanai, T., Watanabe, M., Hayashi, A., Nakazawa, A., Yajima, T., Okazawa, A., et al. (2000). Regulatory effect of interleukin-4 and interleukin-13 on colon cancer cell adhesion. British Journal of Cancer, 82, 1717–723.PubMedCrossRefGoogle Scholar
  299. 299.
    Skinnider, B. F., Kapp, U., & Mak, T. W. (2001). Interleukin 13: A growth factor in hodgkin lymphoma. International Archives of Allergy and Immunology, 126, 267–76.PubMedCrossRefGoogle Scholar
  300. 300.
    Benchetrit, F., Ciree, A., Vives, V., Warnier, G., Gey, A., Sautes-Fridman, C., et al. (2002). Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood, 99, 2114–121.PubMedCrossRefGoogle Scholar
  301. 301.
    Cao, R., Farnebo, J., Kurimoto, M., & Cao, Y. (1999). Interleukin-18 acts as an angiogenesis and tumor suppressor. FASEB Journal, 13, 2195–202.PubMedGoogle Scholar
  302. 302.
    Lin, E. Y., Gouon-Evans, V., Nguyen, A. V., & Pollard, J. W. (2002). The macrophage growth factor CSF-1 in mammary gland development and tumor progression. Journal of Mammary Gland Biology and Neoplasia, 7, 147–62.PubMedCrossRefGoogle Scholar
  303. 303.
    Mroczko, B., Groblewska, M., Wereszczynska-Siemiatkowska, U., Okulczyk, B., Kedra, B., Laszewicz, W., et al. (2007). Serum macrophage-colony stimulating factor levels in colorectal cancer patients correlate with lymph node metastasis and poor prognosis. Clinica Chimica Acta, 380, 208–12.CrossRefGoogle Scholar
  304. 304.
    Menetrier-Caux, C., Thomachot, M. C., Alberti, L., Montmain, G., & Blay, J. Y. (2001). IL-4 prevents the blockade of dendritic cell differentiation induced by tumor cells. Cancer Research, 61, 3096–104.PubMedGoogle Scholar
  305. 305.
    Masson, V., de la Ballina, L. R., Munaut, C., Wielockx, B., Jost, M., Maillard, C., et al. (2005). Contribution of host MMP-2 and MMP-9 to promote tumor vascularization and invasion of malignant keratinocytes. FASEB Journal, 19, 234–36.PubMedGoogle Scholar
  306. 306.
    Yang, L., DeBusk, L. M., Fukuda, K., Fingleton, B., Green-Jarvis, B., Shyr, Y., et al. (2004). Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell, 6, 409–21.PubMedCrossRefGoogle Scholar
  307. 307.
    Kerkela, E., la-aho, R., Klemi, P., Grenman, S., Shapiro, S. D., Kahari, V. M., et al. (2002). Metalloelastase (MMP-12) expression by tumour cells in squamous cell carcinoma of the vulva correlates with invasiveness, while that by macrophages predicts better outcome. Journal of Pathology, 198, 258–69.PubMedCrossRefGoogle Scholar
  308. 308.
    Bingle, L., Brown, N. J., & Lewis, C. E. (2002). The role of tumour-associated macrophages in tumour progression: Implications for new anticancer therapies. Journal of Pathology, 196, 254–65.PubMedCrossRefGoogle Scholar
  309. 309.
    Bogdan, C. (2001). Nitric oxide and the immune response. Nature Immunology, 2, 907–16.PubMedCrossRefGoogle Scholar
  310. 310.
    Mazzoni, A., Bronte, V., Visintin, A., Spitzer, J. H., Apolloni, E., Serafini, P., et al. (2002). Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. Journal of Immunology, 168, 689–95.Google Scholar
  311. 311.
    Wu, S., Boyer, C. M., Whitaker, R. S., Berchuck, A., Wiener, J. R., Weinberg, J. B., et al. (1993). Tumor necrosis factor alpha as an autocrine and paracrine growth factor for ovarian cancer: Monokine induction of tumor cell proliferation and tumor necrosis factor alpha expression. Cancer Research, 53, 1939–944.PubMedGoogle Scholar
  312. 312.
    Mooradian, D. L., Purchio, A. F., & Furcht, L. T. (1990). Differential effects of transforming growth factor beta 1 on the growth of poorly and highly metastatic murine melanoma cells. Cancer Research, 50, 273–77.PubMedGoogle Scholar
  313. 313.
    Csiszar, A., Szentes, T., Haraszti, B., Zou, W., Emilie, D., Petranyi, G., et al. (2001). Characterisation of cytokine mRNA expression in tumour-infiltrating mononuclear cells and tumour cells freshly isolated from human colorectal carcinomas. European Cytokine Network, 12, 87–6.PubMedGoogle Scholar
  314. 314.
    Leibovich, S. J., Polverini, P. J., Shepard, H. M., Wiseman, D. M., Shively, V., & Nuseir, N. (1987). Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha. Nature, 329, 630–32.PubMedCrossRefGoogle Scholar
  315. 315.
    Griffith, T. S., Wiley, S. R., Kubin, M. Z., Sedger, L. M., Maliszewski, C. R., & Fanger, N. A. (1999). Monocyte-mediated tumoricidal activity via the tumor necrosis factor-related cytokine, TRAIL. Journal of Experimental Medicine, 189, 1343–354.PubMedCrossRefGoogle Scholar
  316. 316.
    Kemp, T. J., Elzey, B. D., & Griffith, T. S. (2003). Plasmacytoid dendritic cell-derived IFN-alpha induces TNF-related apoptosis-inducing ligand/Apo-2L-mediated antitumor activity by human monocytes following CpG oligodeoxynucleotide stimulation. Journal of Immunology, 171, 212–18.Google Scholar
  317. 317.
    Bachelder, R. E., Wendt, M. A., & Mercurio, A. M. (2002). Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4. Cancer Research, 62, 7203–206.PubMedGoogle Scholar
  318. 318.
    Senger, D. R., Van de, W. L., Brown, L. F., Nagy, J. A., Yeo, K. T., Yeo, T. K., et al. (1993). Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer and Metastasis Reviews, 12, 303–24.PubMedCrossRefGoogle Scholar
  319. 319.
    Takahashi, Y., Kitadai, Y., Bucana, C. D., Cleary, K. R., & Ellis, L. M. (1995). Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Research, 55, 3964–968.PubMedGoogle Scholar
  320. 320.
    Gabrilovich, D. I., Corak, J., Ciernik, I. F., Kavanaugh, D., & Carbone, D. P. (1997). Decreased antigen presentation by dendritic cells in patients with breast cancer. Clinical Cancer Research, 3, 483–90.PubMedGoogle Scholar
  321. 321.
    Takahashi, A., Kono, K., Ichihara, F., Sugai, H., Fujii, H., & Matsumoto, Y. (2004). Vascular endothelial growth factor inhibits maturation of dendritic cells induced by lipopolysaccharide, but not by proinflammatory cytokines. Cancer Immunology and Immunotherapy, 53, 543–50.PubMedCrossRefGoogle Scholar
  322. 322.
    Lee, A. H., Happerfield, L. C., Bobrow, L. G., & Millis, R. R. (1997). Angiogenesis and inflammation in invasive carcinoma of the breast. Journal of Clinical Pathology, 50, 669–73.PubMedCrossRefGoogle Scholar
  323. 323.
    Volodko, N., Reiner, A., Rudas, M., & Jackesz, R. (1998). Tumor-asscoiated macrophages in breast cancer and their prognostic correlations. The Breast, 7, 99–05.CrossRefGoogle Scholar
  324. 324.
    Goede, V., Brogelli, L., Ziche, M., & Augustin, H. G. (1999). Induction of inflammatory angiogenesis by monocyte chemoattractant protein-1. International Journal of Cancer, 82, 765–70.CrossRefGoogle Scholar
  325. 325.
    Salvesen, H. B., & Akslen, L. A. (1999). Significance of tumour-associated macrophages, vascular endothelial growth factor and thrombospondin-1 expression for tumour angiogenesis and prognosis in endometrial carcinomas. International Journal of Cancer, 84, 538–43.CrossRefGoogle Scholar
  326. 326.
    Forssell, J., Oberg, A., Henriksson, M. L., Stenling, R., Jung, A., & Palmqvist, R. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clinical Cancer Research, 13, 1472–479 (2007).PubMedCrossRefGoogle Scholar
  327. 327.
    Funada, Y., Noguchi, T., Kikuchi, R., Takeno, S., Uchida, Y., & Gabbert, H. E. (2003). Prognostic significance of CD8+ T cell and macrophage peritumoral infiltration in colorectal cancer. Oncology Reports, 10, 309–13.PubMedGoogle Scholar
  328. 328.
    Ohno, S., Ohno, Y., Suzuki, N., Kamei, T., Koike, K., Inagawa, H., et al. (2004). Correlation of histological localization of tumor-associated macrophages with clinicopathological features in endometrial cancer. Anticancer Research, 24, 3335–342.PubMedGoogle Scholar
  329. 329.
    Koide, N., Nishio, A., Sato, T., Sugiyama, A., & Miyagawa, S. (2004). Significance of macrophage chemoattractant protein-1 expression and macrophage infiltration in squamous cell carcinoma of the esophagus. American Journal of Gastroenterology, 99, 1667–674.PubMedCrossRefGoogle Scholar
  330. 330.
    Farinha, P., Masoudi, H., Skinnider, B. F., Shumansky, K., Spinelli, J. J., Gill, K., et al. (2005). Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). Blood, 106, 2169–174.PubMedCrossRefGoogle Scholar
  331. 331.
    Rossi, M. L., Jones, N. R., Candy, E., Nicoll, J. A., Compton, J. S., Hughes, J. T., et al. (1989). The mononuclear cell infiltrate compared with survival in high-grade astrocytomas. Acta Neuropathologica (Berl), 78, 189–93.CrossRefGoogle Scholar
  332. 332.
    Makitie, T., Summanen, P., Tarkkanen, A., & Kivela, T. (2001). Tumor-infiltrating macrophages (CD68(+) cells) and prognosis in malignant uveal melanoma. Investigative Ophthalmology & Visual Science, 42, 1414–421.Google Scholar
  333. 333.
    Piras, F., Colombari, R., Minerba, L., Murtas, D., Floris, C., Maxia, C., et al. (2005). The predictive value of CD8, CD4, CD68, and human leukocyte antigen-D-related cells in the prognosis of cutaneous malignant melanoma with vertical growth phase. Cancer, 104, 1246–254.PubMedCrossRefGoogle Scholar
  334. 334.
    Koukourakis, M. I., Giatromanolaki, A., Kakolyris, S., O’Byrne, K. J., Apostolikas, N., Skarlatos, J., et al. (1998). Different patterns of stromal and cancer cell thymidine phosphorylase reactivity in non-small-cell lung cancer: Impact on tumour neoangiogenesis and survival. British Journal of Cancer, 77, 1696–703.PubMedGoogle Scholar
  335. 335.
    Kerr, K. M., Johnson, S. K., King, G., Kennedy, M. M., Weir, J., & Jeffrey, R. (1998). Partial regression in primary carcinoma of the lung: Does it occur? Histopathology, 33, 55–3.PubMedGoogle Scholar
  336. 336.
    Shimura, S., Yang, G., Ebara, S., Wheeler, T. M., Frolov, A., & Thompson, T. C. (2000). Reduced infiltration of tumor-associated macrophages in human prostate cancer: Association with cancer progression. Cancer Research, 60, 5857–861.PubMedGoogle Scholar
  337. 337.
    Ohno, S., Inagawa, H., Dhar, D. K., Fujii, T., Ueda, S., Tachibana, M., et al. (2003). The degree of macrophage infiltration into the cancer cell nest is a significant predictor of survival in gastric cancer patients. Anticancer Research, 23, 5015–022.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • James E. Talmadge
    • 1
  • Moses Donkor
    • 1
  • Eric Scholar
    • 2
  1. 1.Laboratory of Transplantation Immunology, Department of Pathology and MicrobiologyUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Department of Pharmacology and Experimental NeuroscienceUniversity of Nebraska Medical CenterOmahaUSA

Personalised recommendations