Dendritic Cell Maturation Versus Polarization in Tumor Escape

  • Michael W. Lipscomb
  • Walter J. Storkus
  • Amy K. Wesa


Dendritic cells serve as key immunosurveillance agents throughout the body and orchestrate the coordinate innate and adaptive immune responses to antigenically complex cells and organisms that challenge the host. The ability of dendritic cells to promote beneficial versus irrelevant or even, counterproductive, immunity in the cancer setting depends to a large degree on the operational parameters displayed by the heterogeneous population of dendritic cells found in the tumor microenvironment. This chapter will discuss how tumors manipulate the state of maturation and type of functional polarization displayed by dendritic cells in order to affect immune escape.


Dendritic Cell Antitumor Immune Response Dendritic Cell Maturation Tumor Escape Dendritic Cell Subset 
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. Bell, D., Chomarat, P., Broyles, D., Netto, G., Harb, G. M., Lebecque, S., Valladeau, J., Davoust, J., Palucka, K. A. and Banchereau, J. 1999. In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med 190:1417–1426.PubMedCrossRefGoogle Scholar
  2. Bergeron, A., El-Hage, F., Kambouchner, M., Lecossier, D. and Tazi, A. 2006. Characterisation of dendritic cell subsets in lung cancer micro-environments. Eur Respir J 28:1170–1177.PubMedCrossRefGoogle Scholar
  3. Carlos, C. A., Dong, H. F., Howard, O. M., Oppenheim, J. J., Hanisch, F. G. and Finn, O. J. 2005. Human tumor antigen MUC1 is chemotactic for immature dendritic cells and elicits maturation but does not promote Th1 type immunity. J Immunol 175:1628–1635.PubMedGoogle Scholar
  4. Caux, C., Ait-Yahia, S., Chemin, K., de Bouteiller, O., Dieu-Nosjean, M. C., Homey, B., Massacrier, C., Vanbervliet, B., Zlotnik, A. and Vicari, A. 2000. Dendritic cell biology and regulation of dendritic cell trafficking by chemokines. Springer Semin Immunopathol 22:345–369.PubMedCrossRefGoogle Scholar
  5. Chaux, P., Favre, N., Martin, M. and Martin, F. 1997. Tumor-infiltrating dendritic cells are defective in their antigen-presenting function and inducible B7 expression in rats. Int J Cancer 72:619–624.PubMedCrossRefGoogle Scholar
  6. Colonna, M., Trinchieri, G. and Liu, Y. J. 2004. Plasmacytoid dendritic cells in immunity. Nat Immunol 5:1219–1226.PubMedCrossRefGoogle Scholar
  7. Condeelis, J. and Pollard, J. W. 2006. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266.PubMedCrossRefGoogle Scholar
  8. Curiel, T. J. 2007. Tregs and rethinking cancer immunotherapy. J Clin Invest 117:1167–1174.PubMedCrossRefGoogle Scholar
  9. Danna, E. A., Sinha, P., Gilbert, M., Clements, V. K., Pulaski, B. A. and Ostrand-Rosenberg, S. 2004. Surgical removal of primary tumor reverses tumor-induced immunosuppression despite the presence of metastatic disease. Cancer Res 64:2205–2211.PubMedCrossRefGoogle Scholar
  10. de Jong, E. C., Smits, H. H. and Kapsenberg, M. L. 2005. Dendritic cell-mediated T cell polarization. Springer Semin Immunopathol 26:289–307.PubMedCrossRefGoogle Scholar
  11. Dikov, M. M., Ohm, J. E., Ray, N., Tchekneva, E. E., Burlison, J., Moghanaki, D., Nadaf, S. and Carbone, D. P. 2005. Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. J Immunol 174:215–222.PubMedGoogle Scholar
  12. Doyen, V., Rubio, M., Braun, D., Nakajima, T., Abe, J., Saito, H., Delespesse, G. and Sarfati, M. 2003. Thrombospondin 1 is an autocrine negative regulator of human dendritic cell activation. J Exp Med 198:1277–1283.PubMedCrossRefGoogle Scholar
  13. Esche, C., Lokshin, A., Shurin, G. V., Gastman, B. R., Rabinowich, H., Watkins, S. C., Lotze, M. T. and Shurin, M. R. 1999. Tumor's other immune targets: dendritic cells. J Leukoc Biol 66:336–344.PubMedGoogle Scholar
  14. Evel-Kabler, K., Song, X. T., Aldrich, M., Huang, X. F. and Chen, S. Y. 2006. SOCS1 restricts dendritic cells' ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling. J Clin Invest 116:90–100.PubMedCrossRefGoogle Scholar
  15. 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
  16. Feijoo, E., Alfaro, C., Mazzolini, G., Serra, P., Penuelas, I., Arina, A., Huarte, E., Tirapu, I., Palencia, B., Murillo, O., Ruiz, J., Sangro, B., Richter, J. A., Prieto, J. and Melero, I. 2005. Dendritic cells delivered inside human carcinomas are sequestered by interleukin-8. Int J Cancer 116:275–281.PubMedCrossRefGoogle Scholar
  17. Fricke, I. and Gabrilovich, D. I. 2006. Dendritic cells and tumor microenvironment: a dangerous liaison. Immunol Invest 35:459–483.PubMedCrossRefGoogle Scholar
  18. Gabrilovich, D. 2004. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 4:941–952.PubMedCrossRefGoogle Scholar
  19. Gulubova, M., Manolova, I., Cirowski, G., et al. 2008. Recruitment of dendritic cells in human liver with metastases. Clin Exp Metastasis 25:777–785, [Epub ahead of print].PubMedCrossRefGoogle Scholar
  20. Hanada, T., Tanaka, K., Matsumura, Y., Yamauchi, M., Nishinakamura, H., Aburatani, H., Mashima, R., Kubo, M., Kobayashi, T. and Yoshimura, A. 2005. Induction of hyper Th1 cell-type immune responses by dendritic cells lacking the suppressor of cytokine signaling-1 gene. J Immunol 174:4325–4332.PubMedGoogle Scholar
  21. Hegde, S., Pahne, J. and Smola-Hess, S. 2004. Novel immunosuppressive properties of interleukin-6 in dendritic cells: inhibition of NF-kappaB binding activity and CCR7 expression. Faseb J 18:1439–1441.PubMedGoogle Scholar
  22. Huang, B., Lei, Z., Zhao, J., Gong, W., Liu, J., Chen, Z., Liu, Y., Li, D., Yuan, Y., Zhang, G. M. and Feng, Z. H. 2007. CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Lett 252:86–92.PubMedCrossRefGoogle Scholar
  23. Iero, M., Valenti, R., Huber, V., Filipazzi, P., Parmiani, G., Fais, S. and Rivoltini, L. 2008. Tumour-released exosomes and their implications in cancer immunity. Cell Death Differ 15:80–88.PubMedCrossRefGoogle Scholar
  24. Inokuma, M., dela Rosa, C., Schmitt, C., Haaland, P., Siebert, J., Petry, D., Tang, M., Suni, M. A., Ghanekar, S. A., Gladding, D., Dunne, J. F., Maino, V. C., Disis, M. L. and Maecker, H. T. 2007. Functional T cell responses to tumor antigens in breast cancer patients have a distinct phenotype and cytokine signature. J Immunol 179:2627–2633.PubMedGoogle Scholar
  25. Iwamoto, M., Shinohara, H., Miyamoto, A., Okuzawa, M., Mabuchi, H., Nohara, T., Gon, G., Toyoda, M. and Tanigawa, N. 2003. Prognostic value of tumor-infiltrating dendritic cells expressing CD83 in human breast carcinomas. Int J Cancer 104:92–97.PubMedCrossRefGoogle Scholar
  26. Jackson, S. H., Yu, C. R., Mahdi, R. M., Ebong, S. and Egwuagu, C. E. 2004. Dendritic cell maturation requires STAT1 and is under feedback regulation by suppressors of cytokine signaling. J Immunol 172:2307–2315.PubMedGoogle Scholar
  27. Janssen, E. M., Lemmens, E. E., Wolfe, T., Christen, U., von Herrath, M. G. and Schoenberger, S. P. 2003. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421:852–856.PubMedCrossRefGoogle Scholar
  28. Kapsenberg, M. L. 2003. Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 3:984–993.PubMedCrossRefGoogle Scholar
  29. Kim, R., Emi, M. and Tanabe, K. 2006a. Functional roles of immature dendritic cells in impaired immunity of solid tumour and their targeted strategies for provoking tumour immunity. Clin Exp Immunol 146:189–196.PubMedCrossRefGoogle Scholar
  30. Kim, R., Emi, M., Tanabe, K. and Arihiro, K. 2006b. Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res 66:5527–5536.PubMedCrossRefGoogle Scholar
  31. Kortylewski, M., Jove, R. and Yu, H. 2005. Targeting STAT3 affects melanoma on multiple fronts. Cancer Metastasis Rev 24:315–327.PubMedCrossRefGoogle Scholar
  32. Larmonier, N., Marron, M., Zeng, Y., Cantrell, J., Romanoski, A., Sepassi, M., Thompson, S., Chen, X., Andreansky, S. and Katsanis, E. 2007. Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10. Cancer Immunol Immunother 56:48–59.PubMedCrossRefGoogle Scholar
  33. Li, L., Li, S. P., Min, J. and Zheng, L. 2007. Hepatoma cells inhibit the differentiation and maturation of dendritic cells and increase the production of regulatory T cells. Immunol Lett 114:38–45.PubMedCrossRefGoogle Scholar
  34. Li, Y., Chu, N., Rostami, A. and Zhang, G. X. 2006. Dendritic cells transduced with SOCS-3 exhibit a tolerogenic/DC2 phenotype that directs type 2 Th cell differentiation in vitro and in vivo. J Immunol 177:1679–1688.PubMedGoogle Scholar
  35. Mantovani, A., Schioppa, T., Porta, C., Allavena, P. and Sica, A. 2006. Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev 25:315–322.PubMedCrossRefGoogle Scholar
  36. Marigo, I., Dolcetti, L., Serafini, P., Zanovello, P. and Bronte, V. 2008. Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev 222:162–179.PubMedCrossRefGoogle Scholar
  37. Marteau, F., Gonzalez, N. S., Communi, D., Goldman, M., Boeynaems, J. M. and Communi, D. 2005. Thrombospondin-1 and indoleamine 2,3-dioxygenase are major targets of extracellular ATP in human dendritic cells. Blood 106:3860–3866.PubMedCrossRefGoogle Scholar
  38. Mellor, A. L., Baban, B., Chandler, P., Marshall, B., Jhaver, K., Hansen, A., Koni, P. A., Iwashima, M. and Munn, D. H. 2003. Cutting edge: induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J Immunol 171:1652–1655.PubMedGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 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
  41. Murdoch, C., Muthana, M., Coffelt, S. B. and Lewis, C. E. 2008. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8:618–631.PubMedCrossRefGoogle Scholar
  42. Nagorsen, D., Voigt, S., Berg, E., Stein, H., Thiel, E. and Loddenkemper, C. 2007. Tumor-infiltrating macrophages and dendritic cells in human colorectal cancer: relation to local regulatory T cells, systemic T-cell response against tumor-associated antigens and survival. J Transl Med 5:62.PubMedCrossRefGoogle Scholar
  43. Nefedova, Y., Huang, M., Kusmartsev, S., Bhattacharya, R., Cheng, P., Salup, R., Jove, R. and Gabrilovich, D. 2004. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J Immunol 172:464–474.PubMedGoogle Scholar
  44. Perrot, I., Blanchard, D., Freymond, N., Isaac, S., Guibert, B., Pacheco, Y. and Lebecque, S. 2007. Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage. J Immunol 178:2763–2769.PubMedGoogle Scholar
  45. Piconese, S., Valzasina, B. and Colombo, M. P. 2008. OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J Exp Med 205:825–839.PubMedCrossRefGoogle Scholar
  46. Pinzon-Charry, A., Maxwell, T. and Lopez, J. A. 2005. Dendritic cell dysfunction in cancer: a mechanism for immunosuppression. Immunol Cell Biol 83:451–461.PubMedCrossRefGoogle Scholar
  47. Pirtskhalaishvili, G., Shurin, G. V., Esche, C., Cai, Q., Salup, R. R., Bykovskaia, S. N., Lotze, M. T. and Shurin, M. R. 2000. Cytokine-mediated protection of human dendritic cells from prostate cancer-induced apoptosis is regulated by the Bcl-2 family of proteins. Br J Cancer 83:506–513.PubMedCrossRefGoogle Scholar
  48. Popov, A. and Schultze, J. L. 2008. IDO-expressing regulatory dendritic cells in cancer and chronic infection. J Mol Med 86:145–160.PubMedCrossRefGoogle Scholar
  49. Rabinovich, G. A., Gabrilovich, D. and Sotomayor, E. M. 2007. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267–296.PubMedCrossRefGoogle Scholar
  50. Rutella, S., Danese, S. and Leone, G. 2006. Tolerogenic dendritic cells: cytokine modulation comes of age. Blood 108:1435–1440.PubMedCrossRefGoogle Scholar
  51. 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.PubMedCrossRefGoogle Scholar
  52. Shortman, K. and Naik, S. H. 2007. Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol 7:19–30.PubMedCrossRefGoogle Scholar
  53. Shurin, M. R. and Gabrilovich, D. I. 2001. Regulation of dendritic cell system by tumor. Cancer Res Ther Control 11:65–78.Google Scholar
  54. Shurin, G. V., Shurin, M. R., Bykovskaia, S., Shogan, J., Lotze, M. T. and Barksdale, E. M., Jr. 2001. Neuroblastoma-derived gangliosides inhibit dendritic cell generation and function. Cancer Res 61:363–369.PubMedGoogle Scholar
  55. 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
  56. Steinbrink, K., Jonuleit, H., Muller, G., Schuler, G., Knop, J. and Enk, A. H. 1999. Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells. Blood 93:1634–1642.PubMedGoogle Scholar
  57. Stoitzner, P., Green, L. K., Jung, J. Y., Price, K. M., Atarea, H., Kivell, B. and Ronchese, F. 2008. Inefficient presentation of tumor-derived antigen by tumor-infiltrating dendritic cells. Cancer Immunol Immunother 57:1665–1673.PubMedCrossRefGoogle Scholar
  58. Suzuki, A., Masuda, A., Nagata, H., Kameoka, S., Kikawada, Y., Yamakawa, M. and Kasajima, T. 2002. Mature dendritic cells make clusters with T cells in the invasive margin of colorectal carcinoma. J Pathol 196:37–43.PubMedCrossRefGoogle Scholar
  59. Takahashi, A., Kono, K., Itakura, J., Amemiya, H., Feng Tang, R., Iizuka, H., Fujii, H. and Matsumoto, Y. 2002. Correlation of vascular endothelial growth factor-C expression with tumor-infiltrating dendritic cells in gastric cancer. Oncology 62:121–127.PubMedCrossRefGoogle Scholar
  60. Tatsumi, T., Herrem, C. J., Olson, W. C., Finke, J. H., Bukowski, R. M., Kinch, M. S., Ranieri, E. and Storkus, W. J. 2003. Disease stage variation in CD4+ and CD8+ T-cell reactivity to the receptor tyrosine kinase EphA2 in patients with renal cell carcinoma. Cancer Res 63:4481–4489.PubMedGoogle Scholar
  61. Tatsumi, T., Kierstead, L. S., Ranieri, E., Gesualdo, L., Schena, F. P., Finke, J. H., Bukowski, R. M., Mueller-Berghaus, J., Kirkwood, J. M., Kwok, W. W. and Storkus, W. J. 2002. Disease-associated bias in T helper type 1 (Th1)/Th2 CD4(+) T cell responses against MAGE-6 in HLA-DRB10401(+) patients with renal cell carcinoma or melanoma. J Exp Med 196:619–628.PubMedCrossRefGoogle Scholar
  62. Terme, M., Chaput, N., Combadiere, B., Ma, A., Ohteki, T. and Zitvogel, L. 2008. Regulatory T cells control dendritic cell/NK cell cross-talk in lymph nodes at the steady state by inhibiting CD4+ self-reactive T cells. J Immunol 180:4679–4686.PubMedGoogle Scholar
  63. Tirapu, I., Huarte, E., Guiducci, C., Arina, A., Zaratiegui, M., Murillo, O., Gonzalez, A., Berasain, C., Berraondo, P., Fortes, P., Prieto, J., Colombo, M. P., Chen, L. and Melero, I. 2006. Low surface expression of B7-1 (CD80) is an immunoescape mechanism of colon carcinoma. Cancer Res 66:2442–2450.PubMedCrossRefGoogle Scholar
  64. Troy, A. J., Summers, K. L., Davidson, P. J., Atkinson, C. H. and Hart, D. N. 1998. Minimal recruitment and activation of dendritic cells within renal cell carcinoma. Clin Cancer Res 4:585–593.PubMedGoogle Scholar
  65. Valenti, R., Huber, V., Iero, M., Filipazzi, P., Parmiani, G. and Rivoltini, L. 2007. Tumor-released microvesicles as vehicles of immunosuppression. Cancer Res 67:2912–2915.PubMedCrossRefGoogle Scholar
  66. 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.PubMedCrossRefGoogle Scholar
  67. 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
  68. Wilkin, F., Stordeur, P., Goldman, M., Boeynaems, J. M. and Robaye, B. 2002. Extracellular adenine nucleotides modulate cytokine production by human monocyte-derived dendritic cells: dual effect on IL-12 and stimulation of IL-10. Eur J Immunol 32:2409–2417.PubMedCrossRefGoogle Scholar
  69. Wojas, K., Tabarkiewicz, J., Jankiewicz, M. and Rolinski, J. 2004. Dendritic cells in peripheral blood of patients with breast and lung cancer – a pilot study. Folia Histochem Cytobiol 42:45–48.PubMedGoogle Scholar
  70. Yang, L. and Carbone, D. P. 2004. Tumor-host immune interactions and dendritic cell dysfunction. Adv Cancer Res 92:13–27.PubMedCrossRefGoogle Scholar
  71. Yu, H., Kortylewski, M. and Pardoll, D. 2007. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7:41–51.PubMedCrossRefGoogle Scholar
  72. Zou, W., Machelon, V., Coulomb-L'Hermin, A., Borvak, J., Nome, F., Isaeva, T., Wei, S., Krzysiek, R., Durand-Gasselin, I., Gordon, A., Pustilnik, T., Curiel, D. T., Galanaud, P., Capron, F., Emilie, D. and Curiel, T. J. 2001. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat Med 7:1339–1346.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Michael W. Lipscomb
  • Walter J. Storkus
  • Amy K. Wesa
    • 1
  1. 1.Department of DermatologyUniversity of Pittsburgh Medical CenterPittsburghUSA

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