Dendritic Cells: From Inducers of Specific T-Cell Responses to Promoters of Angiogenesis

  • George Coukos
  • Fabian Benencia


Dendritic cells are the most efficient antigen-presenting cells. They capture, process and present antigens to T cells, thus initiating specific immune responses. Taking into account this capability, dendritic cells have been proposed as therapeutic agents against tumors. In recent years other properties of dendritic cells have surfaced. In particular, dendritic cells have been shown to have immunosuppressive properties in some settings and were also capable of inducing proliferation of regulatory T cells. Moreover, it has been shown that dendritic cells are able to generate angiogenic factors and might be able to participate in the angiogenic process. Thus, for tumor therapeutic purposes, further studies on the biology of dendritic cells are necessary in order to generate cells with optimized immunogenic properties, but avoiding a pro-angiogenic profile.


Vascular Endothelial Growth Factor Dendritic Cell Specific Immune Response Plasmacytoid Dendritic Cell 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. Ardavin, C. 2003. Origin, precursors and differentiation of mouse dendritic cells. Nat Rev Immunol 3:582–590.PubMedCrossRefGoogle Scholar
  2. Baban, B., Hansen, A. M., Chandler, P. R., Manlapat, A., Bingaman, A., Kahler, D. J., Munn, D. H. and Mellor, A. L. 2005. A minor population of splenic dendritic cells expressing CD19 mediates IDO-dependent T cell suppression via type I IFN signaling following B7 ligation. Int Immunol 17:909–919.Google Scholar
  3. Bailey, A. S. and Fleming, W. H. 2003. Converging roads: evidence for an adult hemangioblast. Exp Hematol 31:987–993.PubMedGoogle Scholar
  4. Baleeiro, R. B., Anselmo, L. B., Soares, F. A., Pinto, C. A., Ramos, O., Gross, J. L., Haddad, F., Younes, R. N., Tomiyoshi, M. Y., Bergami-Santos, P. C. and Barbuto, J. A. 2008. High frequency of immature dendritic cells and altered in situ production of interleukin-4 and tumor necrosis factor-alpha in lung cancer. Cancer Immunol Immunother 57:1335–1345.PubMedCrossRefGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. Banerjee, D. K., Dhodapkar, M. V., Matayeva, E., Steinman, R. M. and Dhodapkar, K. M. 2006. Expansion of FOXP3high regulatory T cells by human dendritic cells (DCs) in vitro and after injection of cytokine-matured DCs in myeloma patients. Blood 108:2655–2661.PubMedCrossRefGoogle Scholar
  7. Bonasio, R. and von Andrian, U. H. 2006. Generation, migration and function of circulating dendritic cells. Curr Opin Immunol 18:503–511.PubMedCrossRefGoogle Scholar
  8. Conejo-Garcia, J. R., Benencia, F., Courreges, M. C., Kang, E., Mohamed-Hadley, A., Buckanovich, R. J., Holtz, D. O., Jenkins, A., Na, H., Zhang, L., Wagner, D. S., Katsaros, D., Caroll, R. and Coukos, G. 2004. Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat Med 10:950–958.PubMedCrossRefGoogle Scholar
  9. Conejo-Garcia, J. R., Buckanovich, R. J., Benencia, F., Courreges, M. C., Rubin, S. C., Carroll, R. G. and Coukos, G. 2005. Vascular leukocytes contribute to tumor vascularization. Blood 105:679–681.PubMedCrossRefGoogle Scholar
  10. Coukos, G., Benencia, F., Buckanovich, R. J. and Conejo-Garcia, J. R. 2005. The role of dendritic cell precursors in tumour vasculogenesis. Br J Cancer 92:1182– 1187.PubMedCrossRefGoogle Scholar
  11. Curiel, T. J., Cheng, P., Mottram, P., Alvarez, X., Moons, L., Evdemon-Hogan, M., Wei, S., Zou, L., Kryczek, I., Hoyle, G., Lackner, A., Carmeliet, P. and Zou, W. 2004. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer. Cancer Res 64:5535–5538.PubMedCrossRefGoogle Scholar
  12. Diebold, S. S., Montoya, M., Unger, H., Alexopoulou, L., Roy, P., Haswell, L. E., Al-Shamkhani, A., Flavell, R., Borrow, P. and Reis e Sousa, C. 2003. Viral infection switches non-plasmacytoid dendritic cells into high interferon producers. Nature 424:324–328.PubMedCrossRefGoogle Scholar
  13. Djonov, V., Baum, O. and Burri, P. H. 2003. Vascular remodeling by intussusceptive angiogenesis. Cell Tissue Res 314:107–117.PubMedCrossRefGoogle Scholar
  14. Fainaru, O., Adini, A., Benny, O., Adini, I., Short, S., Bazinet, L., Nakai, K., Pravda, E., Hornstein, M. D., D'Amato, R. J. and Folkman, J. 2008. Dendritic cells support angiogenesis and promote lesion growth in a murine model of endometriosis. Faseb J 22:522–529.PubMedCrossRefGoogle Scholar
  15. Fernandez Pujol, B., Lucibello, F. C., Gehling, U. M., Lindemann, K., Weidner, N., Zuzarte, M. L., Adamkiewicz, J., Elsasser, H. P., Muller, R. and Havemann, K. 2000. Endothelial-like cells derived from human CD14 positive monocytes. Differentiation 65:287–300.PubMedCrossRefGoogle Scholar
  16. Fernandez Pujol, B., Lucibello, F. C., Zuzarte, M., Lutjens, P., Muller, R. and Havemann, K. 2001. Dendritic cells derived from peripheral monocytes express endothelial markers and in the presence of angiogenic growth factors differentiate into endothelial-like cells. Eur J Cell Biol 80:99–110.PubMedCrossRefGoogle Scholar
  17. Ferrara, N. 2004. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25:581–611.PubMedCrossRefGoogle Scholar
  18. Ferrara, N. 2005. VEGF as a therapeutic target in cancer. Oncology 69 Suppl 3:11–16.PubMedCrossRefGoogle Scholar
  19. Gabrilovich, D. I., Chen, H. L., Girgis, K. R., Cunningham, H. T., Meny, G. M., Nadaf, S., Kavanaugh, D. and Carbone, D. P. 1996. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2:1096–1103.PubMedCrossRefGoogle Scholar
  20. Gabrilovich, D. I., Ishida, T., Nadaf, S., Ohm, J. E. and Carbone, D. P. 1999. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res 5:2963–2970.PubMedGoogle Scholar
  21. Ghanekar, S. A., Bhatia, S., Ruitenberg, J. J., DeLa Rosa, C., Disis, M. L., Maino, V. C., Maecker, H. T. and Waters, C. A. 2007. Phenotype and in vitro function of mature MDDC generated from cryopreserved PBMC of cancer patients are equivalent to those from healthy donors. J Immune Based Ther Vaccines 5:7.PubMedCrossRefGoogle Scholar
  22. Gigante, M., Mandic, M., Wesa, A. K., Cavalcanti, E., Dambrosio, M., Mancini, V., Battaglia, M., Gesualdo, L., Storkus, W. J. and Ranieri, E. 2008. Interferon-alpha (IFN-alpha)-conditioned DC preferentially stimulate type-1 and limit Treg-type in vitro T-cell responses from RCC patients. J Immunother 31:254–262.PubMedCrossRefGoogle Scholar
  23. Glod, J., Kobiler, D., Noel, M., Koneru, R., Lehrer, S., Medina, D., Maric, D. and Fine, H. A. 2006. Monocytes form a vascular barrier and participate in vessel repair after brain injury. Blood 107:940–946.PubMedCrossRefGoogle Scholar
  24. Gluckman, J. C., Canque, B., Chapuis, F. and Rosenzwajg, M. 1997. In vitro generation of human dendritic cells and cell therapy. Cytokines Cell Mol Ther 3:187–196.PubMedGoogle Scholar
  25. Gottfried, E., Kreutz, M., Haffner, S., Holler, E., Iacobelli, M., Andreesen, R. and Eissner, G. 2007. Differentiation of human tumour-associated dendritic cells into endothelial-like cells: an alternative pathway of tumour angiogenesis. Scand J Immunol 65:329–335.PubMedCrossRefGoogle Scholar
  26. Heath, W. R. and Carbone, F. R. 2001. Cross-presentation, dendritic cells, tolerance and immunity. Annu Rev Immunol 19:47–64.PubMedCrossRefGoogle Scholar
  27. Hieronymus, T., Gust, T. C., Kirsch, R. D., Jorgas, T., Blendinger, G., Goncharenko, M., Supplitt, K., Rose-John, S., Muller, A. M. and Zenke, M. 2005. Progressive and controlled development of mouse dendritic cells from Flt3+CD11b+ progenitors in vitro. J Immunol 174:2552–2562.PubMedGoogle Scholar
  28. Inaba, K., Inaba, M., Romani, N., Aya, H., Deguchi, M., Ikehara, S., Muramatsu, S. and Steinman, R. M. 1992. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med 176:1693–1702.PubMedCrossRefGoogle Scholar
  29. Kenny, P. A., Lee, G. Y. and Bissell, M. J. 2007. Targeting the tumor microenvironment. Front Biosci 12:3468–3474.PubMedCrossRefGoogle Scholar
  30. Lanzavecchia, A. and Sallusto, F. 2001. The instructive role of dendritic cells on T cell responses: lineages, plasticity and kinetics. Curr Opin Immunol 13:291–298.PubMedCrossRefGoogle Scholar
  31. Lee, A. W., Truong, T., Bickham, K., Fonteneau, J. F., Larsson, M., Da Silva, I., Somersan, S., Thomas, E. K. and Bhardwaj, N. 2002. A clinical grade cocktail of cytokines and PGE2 results in uniform maturation of human monocyte-derived dendritic cells: implications for immunotherapy. Vaccine 20 Suppl 4:A8–22.Google Scholar
  32. Lewis, C. E., De Palma, M. and Naldini, L. 2007. Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res 67:8429–8432.PubMedCrossRefGoogle Scholar
  33. Liu, Y. J. 2001. Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell 106:259–262.PubMedCrossRefGoogle Scholar
  34. Liu, Y. J. 2005. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol 23:275–306.PubMedCrossRefGoogle Scholar
  35. Liu, Y. J., Kanzler, H., Soumelis, V. and Gilliet, M. 2001. Dendritic cell lineage, plasticity and cross-regulation. Nat Immunol 2:585–589.PubMedCrossRefGoogle Scholar
  36. Lutz, M. B., Kukutsch, N., Ogilvie, A. L., Rossner, S., Koch, F., Romani, N. and Schuler, G. 1999. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 223:77–92.PubMedCrossRefGoogle Scholar
  37. Lutz, M. B. and Schuler, G. 2002. Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol 23:445–449.PubMedCrossRefGoogle Scholar
  38. Mantovani, A., Sozzani, S., Locati, M., Schioppa, T., Saccani, A., Allavena, P. and Sica, A. 2004. Infiltration of tumours by macrophages and dendritic cells: tumour-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Novartis Found Symp 256:137–145; discussion 146–148, 259–269.PubMedCrossRefGoogle Scholar
  39. Maraskovsky, E., Brasel, K., Teepe, M., Roux, E. R., Lyman, S. D., Shortman, K. and McKenna, H. J. 1996. Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J Exp Med 184:1953–1962.PubMedCrossRefGoogle Scholar
  40. Masurier, C., Pioche-Durieu, C., Colombo, B. M., Lacave, R., Lemoine, F. M., Klatzmann, D. and Guigon, M. 1999. Immunophenotypical and functional heterogeneity of dendritic cells generated from murine bone marrow cultured with different cytokine combinations: implications for anti-tumoral cell therapy. Immunology 96:569–577.PubMedCrossRefGoogle Scholar
  41. Nakai, K., Fainaru, O., Bazinet, L., Pakneshan, P., Benny, O., Pravda, E., Folkman, J. and D'Amato, R. 2008. Dendritic cells augment choroidal neovascularization. Invest Ophthalmol Vis Sci 49:3666–3670.PubMedCrossRefGoogle Scholar
  42. Osada, T., Chong, G., Tansik, R., Hong, T., Spector, N., Kumar, R., Hurwitz, H. I., Dev, I., Nixon, A. B., Lyerly, H. K., Clay, T. and Morse, M. A. 2008. The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol Immunother 57:1115–1124.PubMedCrossRefGoogle Scholar
  43. Papetti, M. and Herman, I. M. 2002. Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol 282:C947–970.PubMedGoogle Scholar
  44. Patan, S. 2000. Vasculogenesis and angiogenesis as mechanisms of vascular network formation, growth and remodeling. J Neurooncol 50:1–15.PubMedCrossRefGoogle Scholar
  45. Penna, G., Vulcano, M., Sozzani, S. and Adorini, L. 2002. Differential migration behavior and chemokine production by myeloid and plasmacytoid dendritic cells. Hum Immunol 63:1164–1171.PubMedCrossRefGoogle Scholar
  46. Rehman, J., Li, J., Orschell, C. M. and March, K. L. 2003. Peripheral blood "endothelial progenitor cells" are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 107:1164–1169.PubMedCrossRefGoogle Scholar
  47. Riboldi, E., Musso, T., Moroni, E., Urbinati, C., Bernasconi, S., Rusnati, M., Adorini, L., Presta, M. and Sozzani, S. 2005. Cutting edge: proangiogenic properties of alternatively activated dendritic cells. J Immunol 175:2788–2792.PubMedGoogle Scholar
  48. Sanchez-Sanchez, N., Riol-Blanco, L., de la Rosa, G., Puig-Kroger, A., Garcia-Bordas, J., Martin, D., Longo, N., Cuadrado, A., Cabanas, C., Corbi, A. L., Sanchez-Mateos, P. and Rodriguez-Fernandez, J. L. 2004. Chemokine receptor CCR7 induces intracellular signaling that inhibits apoptosis of mature dendritic cells. Blood 104:619–625.PubMedCrossRefGoogle Scholar
  49. Schmeisser, A., Garlichs, C. D., Zhang, H., Eskafi, S., Graffy, C., Ludwig, J., Strasser, R. H. and Daniel, W. G. 2001. Monocytes coexpress endothelial and macrophagocytic lineage markers and form cord-like structures in Matrigel under angiogenic conditions. Cardiovasc Res 49:671–680.PubMedCrossRefGoogle Scholar
  50. Shortman, K. and Liu, Y. J. 2002. Mouse and human dendritic cell subtypes. Nat Rev Immunol 2:151–161.PubMedCrossRefGoogle Scholar
  51. Shurin, M. R., Pandharipande, P. P., Zorina, T. D., Haluszczak, C., Subbotin, V. M., Hunter, O., Brumfield, A., Storkus, W. J., Maraskovsky, E. and Lotze, M. T. 1997. FLT3 ligand induces the generation of functionally active dendritic cells in mice. Cell Immunol 179:174–184.PubMedCrossRefGoogle Scholar
  52. Shurin, M. R., Shurin, G. V., Lokshin, A., Yurkovetsky, Z. R., Gutkin, D. W., Chatta, G., Zhong, H., Han, B. and Ferris, R. L. 2006. Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies? Cancer Metastasis Rev 25:333–356.PubMedCrossRefGoogle Scholar
  53. Sozzani, S., Rusnati, M., Riboldi, E., Mitola, S. and Presta, M. 2007. Dendritic cell-endothelial cell cross-talk in angiogenesis. Trends Immunol 28:385–392.PubMedCrossRefGoogle Scholar
  54. Taieb, J., Chaput, N., Menard, C., Apetoh, L., Ullrich, E., Bonmort, M., Pequignot, M., Casares, N., Terme, M., Flament, C., Opolon, P., Lecluse, Y., Metivier, D., Tomasello, E., Vivier, E., Ghiringhelli, F., Martin, F., Klatzmann, D., Poynard, T., Tursz, T., Raposo, G., Yagita, H., Ryffel, B., Kroemer, G. and Zitvogel, L. 2006. A novel dendritic cell subset involved in tumor immunosurveillance. Nat Med 12:214–219.PubMedCrossRefGoogle Scholar
  55. Tian, F., Grimaldo, S., Fujita, M., Cutts, J., Vujanovic, N. L. and Li, L. Y. 2007. The endothelial cell-produced antiangiogenic cytokine vascular endothelial growth inhibitor induces dendritic cell maturation. J Immunol 179:3742–3751.PubMedGoogle Scholar
  56. Vicari, A. P., Chiodoni, C., Vaure, C., Ait-Yahia, S., Dercamp, C., Matsos, F., Reynard, O., Taverne, C., Merle, P., Colombo, M. P., O'Garra, A., Trinchieri, G. and Caux, C. 2002. Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med 196:541–549.PubMedCrossRefGoogle Scholar
  57. Whiteside, T. L. 2006. The role of immune cells in the tumor microenvironment. Cancer Treat Res 130:103–124.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Division of Gynecologic Oncology, Center for Research on Ovarian CancerUniversity of PennsylvaniaPhiladelphiaUSA

Personalised recommendations