Dendritic Cells in Tumor-Draining Lymph Nodes

  • Alistair J. CochranEmail author
  • Rong-Rong Huang
  • Eijun Itakura
  • Jonathan H. Lee
  • Barbara G. Molenkamp


Dendritic cells are neither the most obvious nor the most abundant cells in lymph nodes, but are certainly among the most immunologically influential, acting primarily as highly potent professional antigen-presenting cells that control complex sequences of innate and adaptive immune responses. Immune responses against tumors, immune resistance, and tolerance are initiated in tumor-draining lymph nodes, including sentinel lymph nodes where mature dendritic cells present processed tumor antigens to naïve T cells generating tumor-specific cytotoxic and helper T cells. Dendritic cells in sentinel lymph nodes of cancer patients have maturation defects that influence their function and phenotype. Lymph nodes contain follicular dendritic cells and paracortical dendritic cells (interdigitating dendritic cells). This chapter deals exclusively with the latter. The topic is a research interest for the authors who have published previously on the topic and this review draws extensively on these prior publications.


Dendritic Cell Sentinel Lymph Node Melanoma Patient Primary Melanoma Immature Dendritic Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Amersi, F. F., Terando, A. M., Goto, Y., Scolyer, R. A., Thompson, J. F., Tran, A. N., Faries, M. B., Morton, D. L. and Hoon, D. S. B. 2008. Activation of CCR9/CCL25 in cutaneous melanoma mediates preferential metastasis to the small intestine. Clin Cancer Res 14:638–645.PubMedGoogle Scholar
  2. Banchereau, J., Briere, F., Caux, C., Davoust, J., Lebecque, S., Liu, Y. J., Pulendran, B. and Palucka, K. 2000. Immunobiology of dendritic cells. Annu Rev Immunol 18:767–811.PubMedGoogle Scholar
  3. Bennaceur, K., Popa, I., Portoukalian, J., Berthier-Vergnes, O. and Peguet-Navarro, J. 2006. Melanoma-derived gangliosides impair migratory and antigen-presenting function of human epidermal Langerhans cells and induce their apoptosis. Int Immunol 18:879–886.PubMedGoogle Scholar
  4. Biggs, M. W. and Eiselein, J. E. 2001. Suppression of immune surveillance in melanoma. Med Hypotheses 56:648–652.PubMedGoogle Scholar
  5. Boyano, M. D., Garcia-Vazquez, M. D., Lopez-Michelena, T., Gardeazabal, J., Bilbao, J., Canavate, M. L., Galdeano, A. G., Izu, R., Diaz-Ramon, L., Raton, J. A. and Diaz-Perez, J. L. 2000. Soluble interleukin-2 receptor, intercellular adhesion molecule-1 and interleukin-10 serum levels in patients with melanoma. Br J Cancer 83:847–852.PubMedGoogle Scholar
  6. Cella, M., Jarrossay, D., Facchetti, F., Alebardi, O., Nakajima, H., Lanzavecchia, A. and Colonna, M. 1999. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med 5:919–923.PubMedGoogle Scholar
  7. Chen, Q., Daniel, V., Maher, D. W. and Hersey, P. 1994. Production of IL-10 by melanoma cells: examination of its role in immunosuppression mediated by melanoma. Int J Cancer 56:755–760.PubMedGoogle Scholar
  8. Cochran, A. J., Balda, B. R., Starz, H., Bachter, D., Krag, D. N., Cruse, C. W., Pijpers, R. and Morton, D. L. 2000. The Augsburg Consensus. Techniques of lymphatic mapping, sentinel lymphadenectomy, and completion lymphadenectomy in cutaneous malignancies. Cancer 89:236–241.Google Scholar
  9. Cochran, A. J., Huang, R. R., Lee, J., Itakura, E., Leong, S. P. L. and Essner, R. 2006. Tumour-induced immune modulation of sentinel lymph nodes. Nat Rev Immunol 6:659–670.PubMedGoogle Scholar
  10. Cochran, A. J., Morton, D. L., Stern, S., Lana, A. M. A., Essner, R. and Wen, D. R. 2001. Sentinel lymph nodes show profound downregulation of antigen-presenting cells of the paracortex: implications for tumor biology and treatment. Mod Pathol 14:604–608.PubMedGoogle Scholar
  11. Cochran, A. J., Pihl, E., Wen, D. R., Hoon, D. S. B. and Korn, E. L. 1987. Zoned immune suppression of lymph nodes draining malignant melanoma: histologic and immunohistologic studies. J Natl Cancer Inst 78:399–405.PubMedGoogle Scholar
  12. Cox, K., North, M., Burke, M., Singhal, H., Renton, S., Aqel, N., Islam, S. and Knight, S. C. 2005. Plasmacytoid dendritic cells (PDC) are the major DC subset innately producing cytokines in human lymph nodes. J Leukoc Biol 78:1142–1152.PubMedGoogle Scholar
  13. Dranoff, G. 2002. GM-CSF-based cancer vaccines. Immunol Rev 188:147–154.PubMedGoogle Scholar
  14. Dummer, W., Becker, J. C., Schwaaf, A., Leverkus, M., Moll, T. and Brocker, E. B. 1995. Elevated serum levels of interleukin-10 in patients with metastatic malignant melanoma. Melanoma Res 5:67–68.PubMedGoogle Scholar
  15. Duramad, O., Fearon, K. L., Chan, J. H., Kanzler, H., Marshall, J. D., Coffman, R. L. and Barrat, F. J. 2003. IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences. Blood 102:4487–4492.PubMedGoogle Scholar
  16. Dzionek, A., Inagaki, Y., Okawa, K., Nagafune, J., Rock, J., Sohma, Y., Winkels, G., Zysk, M., Yamaguchi, Y. and Schmitz, J. 2002. Plasmacytoid dendritic cells: from specific surface markers to specific cellular functions. Hum Immunol 63:1133–1148.PubMedGoogle Scholar
  17. Dzionek, A., Sohma, Y., Nagafune, J., Cella, M., Colonna, M., Facchetti, F., Gunther, G., Johnston, I., Lanzavecchia, A., Nagasaka, T., Okada, T., Vermi, W., Winkels, G., Yamamoto, T., Zysk, M., Yamaguchi, Y. and Schmitz, J. 2001. BDCA-2, a novel plasmacytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction. J Exp Med 194:1823–1834.PubMedGoogle Scholar
  18. Elliott, B., Scolyer, R. A., Suciu, S., Lebecque, S., Rimoldi, D., Gugerli, O., Musat, E., Sharma, R. N., Lienard, D., Keilholz, U., Testori, A., Eggermont, A., MacKie, R., Robert, C., Cook, M., Thompson, J. F., Angevin, E. and Spatz, A. 2007. Long-term protective effect of mature DC-LAMP+ dendritic cell accumulation in sentinel lymph nodes containing micrometastatic melanoma. Clin Cancer Res 13:3825–3830.PubMedGoogle Scholar
  19. Facchetti, F., de Wolf-Peeters, C., de Greef, H. and Desmet, V. J. 1984. Langerhans cells in various benign and malignant pigment-cell lesions of the skin. Arch Dermatol Res 276:283–287.PubMedGoogle Scholar
  20. Facchetti, F., de Wolf-Peeters, C., Mason, D. Y., Pulford, K., van den Oord, J. J. and Desmet, V. J. 1988. Plasmacytoid T cells. Immunohistochemical evidence for their monocyte/macrophage origin. Am J Pathol 133:15–21.PubMedGoogle Scholar
  21. Farzad, Z., Cochran, A. J., McBride, W. H., Gray, J. D., Wong, V. and Morton, D. L. 1990. Lymphocyte subset alterations in nodes regional to human melanoma. Cancer Res 50:3585–3588.PubMedGoogle Scholar
  22. Farzad, Z., McBride, W. H., Ogbechi, H., Asnong-Holthoff, C., Morton, D. L. and Cochran, A. J. 1997. Lymphocytes from lymph nodes at different distances from human melanoma vary in their capacity to inhibit/enhance tumor cell growth in vitro. Melanoma Res 7 Suppl 2:S59–65.Google Scholar
  23. Gatter, K. C., Pulford, K. A., Vanstapel, M. J., Roach, B., Mortimer, P., Woolston, R. E., Taylor-Papadimitriou, J., Lane, E. B. and Mason, D. Y. 1984. An immunohistological study of benign and malignant skin tumours: epithelial aspects. Histopathology 8:209–227.PubMedGoogle Scholar
  24. Gazzaniga, S., Bravo, A. I., Guglielmotti, A., van Rooijen, N., Maschi, F., Vecchi, A., Mantovani, A., Mordoh, J. and Wainstok, R. 2007. Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft. J Invest Dermatol 127:2031–2041.PubMedGoogle Scholar
  25. Gerlini, G., Tun-Kyi, A., Dudli, C., Burg, G., Pimpinelli, N. and Nestle, F. O. 2004. Metastatic melanoma secreted IL-10 down-regulates CD1 molecules on dendritic cells in metastatic tumor lesions. Am J Pathol 165:1853–1863.PubMedGoogle Scholar
  26. Gursel, M., Verthelyi, D. and Klinman, D. M. 2002. CpG oligodeoxynucleotides induce human monocytes to mature into functional dendritic cells. Eur J Immunol 32:2617–2622.PubMedGoogle Scholar
  27. Haigh, P. I., Lucci, A., Turner, R. R., Bostick, P. J., Krasne, D. L., Stern, S. L. and Morton, D. L. 2001. Carbon dye histologically confirms the identity of sentinel lymph nodes in cutaneous melanoma. Cancer 92:535–541.PubMedGoogle Scholar
  28. Hawiger, D., Inaba, K., Dorsett, Y., Guo, M., Mahnke, K., Rivera, M., Ravetch, J. V., Steinman, R. M. and Nussenzweig, M. C. 2001. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 194:769–779.PubMedGoogle Scholar
  29. Hoon, D. S. B., Foshag, L. J., Nizze, A. S., Bohman, R. and Morton, D. L. 1990. Suppressor cell activity in a randomized trial of patients receiving active specific immunotherapy with melanoma cell vaccine and low dosages of cyclophosphamide. Cancer Res 50:5358–5364.PubMedGoogle Scholar
  30. Hoon, D. S. B., Korn, E. L. and Cochran, A. J. 1987. Variations in functional immunocompetence of individual tumor-draining lymph nodes in humans. Cancer Res 47:1740–1744.PubMedGoogle Scholar
  31. Huang, R. R., Paul, E., Lin, L. L., Wen, D. R., Itakura, E. and Cochran, A. J. 2005. Sentinel lymph nodes are immunosuppressed whether or not they contain metastatic melanoma. Mod Pathol 18:84A–85A.Google Scholar
  32. Huang, R. R., Turner, R. and Cochran, A. J. 2008. Tumor-free sentinel nodes show immune modulation. Ann Surg Oncol 15:S1.Google Scholar
  33. Huang, R. R., Wen, D. R., Guo, J., Giuliano, A. E., Nguyen, M., Offodile, R., Stern, S., Turner, R. and Cochran, A. J. 2000. Selective modulation of paracortical dendritic cells and T-lymphocytes in breast cancer sentinel lymph nodes. Breast J 6:225–232.PubMedGoogle Scholar
  34. Huang, R. R., Wen, D. R., Itakura, E., Essner, R. and Cochran, A. J. 2004a. Loss of dendritic cell complexity in sentinel nodes correlates with reduced activated T cells. Ann Surg Oncol 11:S3.Google Scholar
  35. Huang, R. R., Wen, D. R., Itakura, E., Turner, R. and Cochran, A. J. 2004b. Does the pathologist have a role in conforming that a node submitted as sentinel is true sentinel? Mod Pathol 17:93A.Google Scholar
  36. Hussein, M. R. 2005. Transforming growth factor-beta and malignant melanoma: molecular mechanisms. J Cutan Pathol 32:389–395.PubMedGoogle Scholar
  37. Ito, T., Kanzler, H., Duramad, O., Cao, W. and Liu, Y. J. 2006. Specialization, kinetics, and repertoire of type 1 interferon responses by human plasmacytoid predendritic cells. Blood 107:2423–2431.PubMedGoogle Scholar
  38. Jandus, C., Bioley, G., Speiser, D. E. and Romero, P. 2008. Selective accumulation of differentiated FOXP3+ CD4+ T cells in metastatic tumor lesions from melanoma patients compared to peripheral blood. Cancer Immunol Immunother 57:1795–1805.PubMedGoogle Scholar
  39. Kawarada, Y., Ganss, R., Garbi, N., Sacher, T., Arnold, B. and Hammerling, G. J. 2001. NK- and CD8+ T cell-mediated eradication of established tumors by peritumoral injection of CpG-containing oligodeoxynucleotides. J Immunol 167:5247–5253.PubMedGoogle Scholar
  40. Kim, R., Emi, M., Tanabe, K. and Arihiro, K. 2006. Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res 66:5527–5536.PubMedGoogle Scholar
  41. Krug, A., Towarowski, A., Britsch, S., Rothenfusser, S., Hornung, V., Bals, R., Giese, T., Engelmann, H., Endres, S., Krieg, A. M. and Hartmann, G. 2001. Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur J Immunol 31:3026–3037.PubMedGoogle Scholar
  42. Krüger-Krasagakes, S., Krasagakis, K., Garbe, C., Schmitt, E., Hüls, C., Blankenstein, T. and Diamantstein, T. 1994. Expression of interleukin 10 in human melanoma. Br J Cancer 70:1182–1185.PubMedGoogle Scholar
  43. Lacal, P. M., Failla, C. M., Pagani, E., Odorisio, T., Schietroma, C., Falcinelli, S., Zambruno, G. and D'Atri, S. 2000. Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor. J Invest Dermatol 115:1000–1007.PubMedGoogle Scholar
  44. Ladanyi, A., Kiss, J., Somlai, B., Gilde, K., Fejos, Z., Mohos, A., Gaudi, I. and Timar, J. 2007. Density of DC-LAMP+ mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor. Cancer Immunol Immunother 56:1459–1469.PubMedGoogle Scholar
  45. Laguens, G., Coronato, S., Laguens, R., Portiansky, E. and Di Girolamo, V. 2002. Human regional lymph nodes draining cancer exhibit a profound dendritic cell depletion as comparing to those from patients without malignancies. Immunol Lett 84:159–162.PubMedGoogle Scholar
  46. Lana, A. M. A., Wen, D. R. and Cochran, A. J. 2001. The morphology, immunophenotype and distribution of paracortical dendritic leucocytes in lymph nodes regional to cutaneous melanoma. Melanoma Res 11:401–410.PubMedGoogle Scholar
  47. Langerhans, P. 1868. Ueber die Nerven der menschlichen Haut. Virchows Archives [Pathol Anat] 44:325–337.Google Scholar
  48. Lee, J. H., Torisu-Itakara, H., Cochran, A. J., Kadison, A., Huynh, Y., Morton, D. L. and Essner, R. 2005. Quantitative analysis of melanoma-induced cytokine-mediated immunosuppression in melanoma sentinel nodes. Clin Cancer Res 11:107–112.PubMedGoogle Scholar
  49. Lee, J. R., Dalton, R. R., Messina, J. L., Sharma, M. D., Smith, D. M., Burgess, R. E., Mazzella, F., Antonia, S. J., Mellor, A. L. and Munn, D. H. 2003. Pattern of recruitment of immunoregulatory antigen-presenting cells in malignant melanoma. Lab Invest 83:1457–1466.PubMedGoogle Scholar
  50. Liu, Y., Zhang, P., Li, J., Kulkarni, A. B., Perruche, S. and Chen, W. 2008. A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat Immunol 9:632–640.PubMedGoogle Scholar
  51. Liyanage, U. K., Goedegebuure, P. S., Moore, T. T., Viehl, C. T., Moo-Young, T. A., Larson, J. W., Frey, D. M., Ehlers, J. P., Eberlein, T. J. and Linehan, D. C. 2006. Increased prevalence of regulatory T cells (Treg) is induced by pancreas adenocarcinoma. J Immunother 29:416–424.PubMedGoogle Scholar
  52. Lucci, A., Turner, R. R. and Morton, D. L. 1999. Carbon dye as an adjunct to isosulfan blue dye for sentinel lymph node dissection. Surgery 126:48–53.PubMedGoogle Scholar
  53. Ludviksson, B. R., Seegers, D., Resnick, A. S. and Strober, W. 2000. The effect of TGF-β on immune responses of naive versus memory CD4+ Th1/Th2 T cells. Eur J Immunol 30:2101–2111.PubMedGoogle Scholar
  54. Luo, X., Tarbell, K. V., Yang, H., Pothoven, K., Bailey, S. L., Ding, R., Steinman, R. M. and Suthanthiran, M. 2007. Dendritic cells with TGF-β differentiate naïve CD4+CD25 T cells into islet-protective Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A 104:2821–2826.PubMedGoogle Scholar
  55. Maeda, H., Kuwahara, H., Ichimura, Y., Ohtsuki, M., Kurakata, S. and Shiraishi, A. 1995. TGF-β enhances macrophage ability to produce IL-10 in normal and tumor-bearing mice. J Immunol 155:4926–4932.PubMedGoogle Scholar
  56. Maeda, H. and Shiraishi, A. 1996. TGF-beta contributes to the shift toward Th2-type responses through direct and IL-10-mediated pathways in tumor-bearing mice. J Immunol 156:73–78.PubMedGoogle Scholar
  57. Mahnke, K., Bedke, T. and Enk, A. H. 2007. Regulatory conversation between antigen presenting cells and regulatory T cells enhance immune suppression. Cell Immunol 250:1–13.PubMedGoogle Scholar
  58. Matsuura, K., Yamaguchi, Y., Ueno, H., Osaki, A., Arihiro, K. and Toge, T. 2006. Maturation of dendritic cells and T-cell responses in sentinel lymph nodes from patients with breast carcinoma. Cancer 106:1227–1236.PubMedGoogle Scholar
  59. Molenkamp, B. G., Sluijter, B. J., van Leeuwen, P. A., Santegoets, S. J. A. M., Meijer, S., Wijnands, P. G. J. T. B., Haanen, J. B. A. G., van den Eertwegh, A. J. M., Scheper, R. J. and de Gruijl, T. D. 2008. Local administration of PF-3512676 CpG-B instigates tumor-specific CD8+ T-cell reactivity in melanoma patients. Clin Cancer Res 14:4532–4542.PubMedGoogle Scholar
  60. Molenkamp, B. G., van Leeuwen, P. A. M., Meijer, S., Sluijter, B. J. R., Wijnands, P. G. J. T. B., Baars, A., van den Eertwegh, A. J. M., Scheper, R. J. and de Gruijl, T. D. 2007. Intradermal CpG-B activates both plasmacytoid and myeloid dendritic cells in the sentinel lymph node of melanoma patients. Clin Cancer Res 13:2961–2969.PubMedGoogle Scholar
  61. Morelli, A. E. and Thomson, A. W. 2007. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol 7:610–621.PubMedGoogle Scholar
  62. Morton, D. L., Hoon, D. S. B., Cochran, A. J., Turner, R. R., Essner, R., Takeuchi, H., Wanek, L. A., Glass, E., Foshag, L. J., Hsueh, E. C., Bilchik, A. J., Elashoff, D. and Elashoff, R. 2003. Lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: therapeutic utility and implications of nodal microanatomy and molecular staging for improving the accuracy of detection of nodal micrometastases. Ann Surg 238:538–549.PubMedGoogle Scholar
  63. Morton, B. A., Ramey, W. G., Paderon, H. and Miller, R. E. 1986. Monoclonal antibody-defined phenotypes of regional lymph node and peripheral blood lymphocyte subpopulations in early breast cancer. Cancer Res 46:2121–2126.PubMedGoogle Scholar
  64. Morton, D. L., Thompson, J. F., Cochran, A. J., Mozzillo, N., Elashoff, R., Essner, R., Nieweg, O. E., Roses, D. F., Hoekstra, H. J., Karakousis, C. P., Reintgen, D. S., Coventry, B. J., Glass, E. C. and Wang, H. J. 2006. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355:1307–1317.PubMedGoogle Scholar
  65. Morton, D. L., Wen, D. R., Wong, J. H., Economou, J. S., Cagle, L. A., Storm, F. K., Foshag, L. J. and Cochran, A. J. 1992. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127:392–399.PubMedGoogle Scholar
  66. Mouawad, R., Khayat, D. and Soubrane, C. 2000. Plasma Fas ligand, an inducer of apoptosis, and plasma soluble Fas, an inhibitor of apoptosis, in advanced melanoma. Melanoma Res 10:461–467.PubMedGoogle Scholar
  67. Movassagh, M., Spatz, A., Davoust, J., Lebecque, S., Romero, P., Pittet, M., Rimoldi, D., Lienard, D., Gugerli, O., Ferradini, L., Robert, C., Avril, M. F., Zitvogel, L. and Angevin, E. 2004. Selective accumulation of mature DC-Lamp+ dendritic cells in tumor sites is associated with efficient T-cell-mediated antitumor response and control of metastatic dissemination in melanoma. Cancer Res 64:2192–2198.PubMedGoogle Scholar
  68. Munn, D. H., Sharma, M. D., Hou, D., Baban, B., Lee, J. R., Antonia, S. J., Messina, J. L., Chandler, P., Koni, P. A. and Mellor, A. L. 2004. Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 114:280–290.PubMedGoogle Scholar
  69. Munn, D. H., Sharma, M. D., Lee, J. R., Jhaver, K. G., Johnson, T. S., Keskin, D. B., Marshall, B., Chandler, P., Antonia, S. J., Burgess, R., Slingluff, C. L., Jr. and Mellor, A. L. 2002. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297:1867–1870.PubMedGoogle Scholar
  70. Munz, C., Steinman, R. M. and Fujii, S. 2005. Dendritic cell maturation by innate lymphocytes: coordinated stimulation of innate and adaptive immunity. J Exp Med 202:203–207.PubMedGoogle Scholar
  71. Murakami, T., Cardones, A. R. and Hwang, S. T. 2004. Chemokine receptors and melanoma metastasis. J Dermatol Sci 36:71–78.PubMedGoogle Scholar
  72. Ohl, L., Mohaupt, M., Czeloth, N., Hintzen, G., Kiafard, Z., Zwirner, J., Blankenstein, T., Henning, G. and Forster, R. 2004. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21:279–288.PubMedGoogle Scholar
  73. Palucka, K. A., Taquet, N., Sanchez-Chapuis, F. and Gluckman, J. C. 1998. Dendritic cells as the terminal stage of monocyte differentiation. J Immunol 160:4587–4595.PubMedGoogle Scholar
  74. Patterson, S. 2000. Flexibility and cooperation among dendritic cells. Nat Immunol 1:273–274.PubMedGoogle Scholar
  75. Payne, A. S. and Cornelius, L. A. 2002. The role of chemokines in melanoma tumor growth and metastasis. J Invest Dermatol 118:915–922.PubMedGoogle Scholar
  76. Pinzon-Charry, A., Maxwell, T., McGuckin, M. A., Schmidt, C., Furnival, C. and Lopez, J. A. 2006. Spontaneous apoptosis of blood dendritic cells in patients with breast cancer. Breast Cancer Res 8:R5.PubMedGoogle Scholar
  77. Polak, M. E., Borthwick, N. J., Gabriel, F. G., Johnson, P., Higgins, B., Hurren, J., McCormick, D., Jager, M. J. and Cree, I. A. 2007a. Mechanisms of local immunosuppression in cutaneous melanoma. Br J Cancer 96:1879–1887.PubMedGoogle Scholar
  78. Polak, M. E., Borthwick, N. J., Johnson, P., Hungerford, J. L., Higgins, B., Di Palma, S., Jager, M. J. and Cree, I. A. 2007b. Presence and phenotype of dendritic cells in uveal melanoma. Br J Ophthalmol 91:971–976.PubMedGoogle Scholar
  79. Pollard, J. W. 2004. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78.PubMedGoogle Scholar
  80. Probst, H. C., McCoy, K., Okazaki, T., Honjo, T. and van den Broek, M. 2005. Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol 6:280–286.PubMedGoogle Scholar
  81. Randolph, G. J., Angeli, V. and Swartz, M. A. 2005. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol 5:617–628.PubMedGoogle Scholar
  82. Redondo, P., Solano, T., B, V. A., Bauza, A. and Idoate, M. 2002. Fas and Fas ligand: expression and soluble circulating levels in cutaneous malignant melanoma. Br J Dermatol 147:80–86.PubMedGoogle Scholar
  83. Salio, M., Cella, M., Vermi, W., Facchetti, F., Palmowski, M. J., Smith, C. L., Shepherd, D., Colonna, M. and Cerundolo, V. 2003. Plasmacytoid dendritic cells prime IFN-γ-secreting melanoma-specific CD8 lymphocytes and are found in primary melanoma lesions. Eur J Immunol 33:1052–1062.PubMedGoogle Scholar
  84. Scala, S., Giuliano, P., Ascierto, P. A., Ierano, C., Franco, R., Napolitano, M., Ottaiano, A., Lombardi, M. L., Luongo, M., Simeone, E., Castiglia, D., Mauro, F., De Michele, I., Calemma, R., Botti, G., Caraco, C., Nicoletti, G., Satriano, R. A. and Castello, G. 2006. Human melanoma metastases express functional CXCR4. Clin Cancer Res 12:2427–2433.PubMedGoogle Scholar
  85. Seo, N., Hayakawa, S., Takigawa, M. and Tokura, Y. 2001. Interleukin-10 expressed at early tumour sites induces subsequent generation of CD4+ T-regulatory cells and systemic collapse of antitumour immunity. Immunology 103:449–457.PubMedGoogle Scholar
  86. Sharma, M. D., Baban, B., Chandler, P., Hou, D. Y., Singh, N., Yagita, H., Azuma, M., Blazar, B. R., Mellor, A. L. and Munn, D. H. 2007. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest 117:2570–2582.PubMedGoogle Scholar
  87. Shields, J. D., Emmett, M. S., Dunn, D. B., Joory, K. D., Sage, L. M., Rigby, H., Mortimer, P. S., Orlando, A., Levick, J. R. and Bates, D. O. 2007. Chemokine-mediated migration of melanoma cells towards lymphatics – a mechanism contributing to metastasis. Oncogene 26:2997–3005.PubMedGoogle Scholar
  88. Shortman, K. and Naik, S. H. 2007. Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol 7:19–30.PubMedGoogle Scholar
  89. Steinman, R. M. and Banchereau, J. 2007. Taking dendritic cells into medicine. Nature 449:419–426.PubMedGoogle Scholar
  90. Steinman, R. M. and Cohn, Z. A. 1973. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med 137:1142–1162.PubMedGoogle Scholar
  91. Stene, M. A., Babajanians, M., Bhuta, S. and Cochran, A. J. 1988. Quantitative alterations in cutaneous Langerhans cells during the evolution of malignant melanoma of the skin. J Invest Dermatol 91:125–128.PubMedGoogle Scholar
  92. Summers, K. L., Hock, B. D., McKenzie, J. L. and Hart, D. N. 2001. Phenotypic characterization of five dendritic cell subsets in human tonsils. Am J Pathol 159:285–295.PubMedGoogle Scholar
  93. Takeuchi, H., Fujimoto, A., Tanaka, M., Yamano, T., Hsueh, E. and Hoon, D. S. B. 2004. CCL21 chemokine regulates chemokine receptor CCR7 bearing malignant melanoma cells. Clin Cancer Res 10:2351–2358.PubMedGoogle Scholar
  94. Torisu, H., Ono, M., Kiryu, H., Furue, M., Ohmoto, Y., Nakayama, J., Nishioka, Y., Sone, S. and Kuwano, M. 2000. Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: possible involvement of TNFα and IL-1α. Int J Cancer 85:182–188.PubMedGoogle Scholar
  95. Torisu-Itakura, H., Lee, J. H., Huynh, Y., Ye, X., Essner, R. and Morton, D. L. 2007a. Monocyte-derived IL-10 expression predicts prognosis of stage IV melanoma patients. J Immunother 30:831–838.PubMedGoogle Scholar
  96. Torisu-Itakura, H., Lee, J. H., Scheri, R. P., Huynh, Y., Ye, X., Essner, R. and Morton, D. L. 2007b. Molecular characterization of inflammatory genes in sentinel and nonsentinel nodes in melanoma. Clin Cancer Res 13:3125–3132.PubMedGoogle Scholar
  97. Ugurel, S., Rappl, G., Tilgen, W. and Reinhold, U. 2001. Increased soluble CD95 (sFas/CD95) serum level correlates with poor prognosis in melanoma patients. Clin Cancer Res 7:1282–1286.PubMedGoogle Scholar
  98. Varney, M. L., Johansson, S. L. and Singh, R. K. 2005a. Tumour-associated macrophage infiltration, neovascularization and aggressiveness in malignant melanoma: role of monocyte chemotactic protein-1 and vascular endothelial growth factor-A. Melanoma Res 15:417–425.PubMedGoogle Scholar
  99. Varney, M. L., Johansson, S. L. and Singh, R. K. 2006. Distinct expression of CXCL8 and its receptors CXCR1 and CXCR2 and their association with vessel density and aggressiveness in malignant melanoma. Am J Clin Pathol 125:209–216.PubMedGoogle Scholar
  100. Varney, M. L., Olsen, K. J., Mosley, R. L. and Singh, R. K. 2005b. Paracrine regulation of vascular endothelial growth factor – a expression during macrophage-melanoma cell interaction: role of monocyte chemotactic protein-1 and macrophage colony-stimulating factor. J Interferon Cytokine Res 25:674–683.PubMedGoogle Scholar
  101. Vermi, W., Bonecchi, R., Facchetti, F., Bianchi, D., Sozzani, S., Festa, S., Berenzi, A., Cella, M. and Colonna, M. 2003. Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas. J Pathol 200:255–268.PubMedGoogle Scholar
  102. Vuylsteke, R. J. C. L. M., Molenkamp, B. G., Gietema, H. A., van Leeuwen, P. A. M., Wijnands, P. G. J. T. B., Vos, W., van Diest, P. J., Scheper, R. J., Meijer, S. and de Gruijl, T. D. 2004. Local administration of granulocyte/macrophage colony-stimulating factor increases the number and activation state of dendritic cells in the sentinel lymph node of early-stage melanoma. Cancer Res 64:8456–8460.PubMedGoogle Scholar
  103. Vuylsteke, R. J. C. L. M., Molenkamp, B. G., van Leeuwen, P. A. M., Meijer, S., Wijnands, P. G. J. T. B., Haanen, J. B. A. G., Scheper, R. J. and de Gruijl, T. D. 2006. Tumor-specific CD8+ T cell reactivity in the sentinel lymph node of GM-CSF-treated stage I melanoma patients is associated with high myeloid dendritic cell content. Clin Cancer Res 12:2826–2833.PubMedGoogle Scholar
  104. Vuylsteke, R. J. C. L. M., van Leeuwen, P. A. M., Meijer, S., Wijnands, P. G. J. T. B., Statius Muller, M. G., Busch, D. H., Scheper, R. J. and de Gruijl, T. D. 2002. Sampling tumor-draining lymph nodes for phenotypic and functional analysis of dendritic cells and T cells. Am J Pathol 161:19–26.PubMedGoogle Scholar
  105. Wen, D. R., Hoon, D. S. B., Chang, C. and Cochran, A. J. 1989. Variations in lymphokine generation by individual lymph nodes draining human malignant tumors. Cancer Immunol Immunother 30:277–282.PubMedGoogle Scholar
  106. Wethmar, K., Helmus, Y., Luhn, K., Jones, C., Laskowska, A., Varga, G., Grabbe, S., Lyck, R., Engelhardt, B., Bixel, M. G., Butz, S., Loser, K., Beissert, S., Ipe, U., Vestweber, D. and Wild, M. K. 2006. Migration of immature mouse DC across resting endothelium is mediated by ICAM-2 but independent of β 2-integrins and murine DC-SIGN homologues. Eur J Immunol 36:2781–2794.PubMedGoogle Scholar
  107. Wiley, H. E., Gonzalez, E. B., Maki, W., Wu, M. T. and Hwang, S. T. 2001. Expression of CC chemokine receptor-7 and regional lymph node metastasis of B16 murine melanoma. J Natl Cancer Inst 93:1638–1643.PubMedGoogle Scholar
  108. Wilson, N. S., El-Sukkari, D., Belz, G. T., Smith, C. M., Steptoe, R. J., Heath, W. R., Shortman, K. and Villadangos, J. A. 2003. Most lymphoid organ dendritic cell types are phenotypically and functionally immature. Blood 102:2187–2194.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Alistair J. Cochran
    • 1
    Email author
  • Rong-Rong Huang
  • Eijun Itakura
  • Jonathan H. Lee
  • Barbara G. Molenkamp
  1. 1.Department of Pathology and Laboratory MedicineDavid Geffen School of Medicine at UCLALos AngelesUSA

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