Transendothelial migration (TEM) of in vitro generated dendritic cell vaccine in cancer immunotherapy

  • Muhammad Umer Ashraf
  • Yideul Jeong
  • Seung-Eon Roh
  • Yong-Soo BaeEmail author


Many efforts have been made to improve the efficacy of dendritic cell (DC) vaccines in DC-based cancer immunotherapy. One of these efforts is to deliver a DC vaccine more efficiently to the regional lymph nodes (rLNs) to induce stronger anti-tumor immunity. Together with chemotaxis, transendothelial migration (TEM) is believed to be a critical and indispensable step for DC vaccine migration to the rLNs after administration. However, the mechanism underlying the in vitro-generated DC TEM in DC-based cancer immunotherapy has been largely unknown. Currently, junctional adhesion molecules (JAMs) were found to play an important role in the TEM of in vitro generated DC vaccines. This paper reviews the TEM of DC vaccines and TEM-associated JAM molecules.


chemotaxis DC vaccine cancer immunotherapy JAMs JAML regional LNs 



This work was supported by a National Research Foundation (NRF) grant funded by the Korea Ministry of Science and ICT (SRC-2017R1A5A1014560) and in part by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (HI16C1074).

Compliance with ethical standards

Conflict of interest

No potential conflict of interest was disclosed.


  1. Ahmed MS, Byeon SE, Jeong Y, Miah MA, Salahuddin M, Lee Y, Park SS, Bae YS (2015) Dab2, a negative regulator of DC immunogenicity, is an attractive molecular target for DC-based immunotherapy. Oncoimmunology 4:e984550CrossRefGoogle Scholar
  2. Alvarez D, Vollmann EH, Von Andrian UH (2008) Mechanisms and consequences of dendritic cell migration. Immunity 29:325–342CrossRefGoogle Scholar
  3. Banchereau J, Palucka AK (2005) Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol 5:296–306CrossRefGoogle Scholar
  4. Barreiro O, Yanez-Mo M, Serrador JM, Montoya MC, Vicente-Manzanares M, Tejedor R, Furthmayr H, Sanchez-Madrid F (2002) Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J Cell Biol 157:1233–1245CrossRefGoogle Scholar
  5. Bazzoni G (2003) The JAM family of junctional adhesion molecules. Curr Opin Cell Biol 15:525–530CrossRefGoogle Scholar
  6. Caux C, Vanbervliet B, Massacrier C, Ait-Yahia S, Vaure C, Chemin K, Dieu-Nosjean MC, Vicari A (2002) Regulation of dendritic cell recruitment by chemokines. Transplantation 73:S7–11CrossRefGoogle Scholar
  7. Cera MR, Del Prete A, Vecchi A, Corada M, Martin-Padura I, Motoike T, Tonetti P, Bazzoni G, Vermi W, Gentili F, Bernasconi S, Sato TN, Mantovani A, Dejana E (2004) Increased DC trafficking to lymph nodes and contact hypersensitivity in junctional adhesion molecule-A-deficient mice. J Clin Invest 114:729–738CrossRefGoogle Scholar
  8. Chen Z, Dehm S, Bonham K, Kamencic H, Juurlink B, Zhang X, Gordon JR, Xiang J (2001) DNA array and biological characterization of the impact of the maturation status of mouse dendritic cells on their phenotype and antitumor vaccination efficacy. Cell Immunol 214:60–71CrossRefGoogle Scholar
  9. Choi EY, Santoso S, Chavakis T (2009) Mechanisms of neutrophil transendothelial migration. Front Biosci (Landmark Ed) 14:1596–1605CrossRefGoogle Scholar
  10. D’amico G, Bianchi G, Bernasconi S, Bersani L, Piemonti L, Sozzani S, Mantovani A, Allavena P (1998) Adhesion, transendothelial migration, and reverse transmigration of in vitro cultured dendritic cells. Blood 92:207–214Google Scholar
  11. Diacovo TG, Blasius AL, Mak TW, Cella M, Colonna M (2005) Adhesive mechanisms governing interferon-producing cell recruitment into lymph nodes. J Exp Med 202:687–696CrossRefGoogle Scholar
  12. Fong L, Brockstedt D, Benike C, Wu L, Engleman EG (2001) Dendritic cells injected via different routes induce immunity in cancer patients. J Immunol 166:4254–4259CrossRefGoogle Scholar
  13. Forster R, Davalos-Misslitz AC, Rot A (2008) CCR13 and its ligands: balancing immunity and tolerance. Nat Rev Immunol 8:362–371CrossRefGoogle Scholar
  14. Guo YL, Bai R, Chen CX, Liu DQ, Liu Y, Zhang CY, Zen K (2009) Role of junctional adhesion molecule-like protein in mediating monocyte transendothelial migration. Arterioscler Thromb Vasc Biol 29:75–83CrossRefGoogle Scholar
  15. Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia A (2001) Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol 31:3388–3393CrossRefGoogle Scholar
  16. Krautwald S, Ziegler E, Forster R, Ohl L, Amann K, Kunzendorf U (2004) Ectopic expression of CCL19 impairs alloimmune response in mice. Immunology 112:301–309CrossRefGoogle Scholar
  17. Lee JH, Lee Y, Lee M, Heo MK, Song JS, Kim KH, Lee H, Yi NJ, Lee KW, Suh KS, Bae YS, Kim YJ (2015) A phase I/IIa study of adjuvant immunotherapy with tumour antigen-pulsed dendritic cells in patients with hepatocellular carcinoma. Br J Cancer 113:1666–1676CrossRefGoogle Scholar
  18. Lee JH, Tak WY, Lee Y, Heo MK, Song JS, Kim HY, Park SY, Bae SH, Heo J, Kim KH, Bae YS, Kim YJ (2017) Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study. Oncoimmunology 6:e1328335CrossRefGoogle Scholar
  19. Ley K (2003) The role of selectins in inflammation and disease. Trends Mol Med 9:263–268CrossRefGoogle Scholar
  20. Ley K, Laudanna C, Cybulsky MI, Nourshargh S (2007) Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 7:678–689CrossRefGoogle Scholar
  21. Linette GP, Carreno BM (2013) Dendritic cell-based vaccines: Shining the spotlight on signal 3. Oncoimmunology 2:e26512CrossRefGoogle Scholar
  22. Luissint AC, Lutz PG, Calderwood DA, Couraud PO, Bourdoulous S (2008) JAM-L-mediated leukocyte adhesion to endothelial cells is regulated in cis by alpha4beta1 integrin activation. J Cell Biol 183:1159–1173CrossRefGoogle Scholar
  23. Luissint AC, Nusrat A, Parkos CA (2014) JAM-related proteins in mucosal homeostasis and inflammation. Semin Immunopathol 36:211–226CrossRefGoogle Scholar
  24. Luster AD, Alon R, Von Andrian UH (2005) Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 6:1182–1190CrossRefGoogle Scholar
  25. Ma J, Wang JH, Guo YJ, Sy MS, Bigby M (1994) In vivo treatment with anti-ICAM-1 and anti-LFA-1 antibodies inhibits contact sensitization-induced migration of epidermal Langerhans cells to regional lymph nodes. Cell Immunol 158:389–399CrossRefGoogle Scholar
  26. Mamdouh Z, Chen X, Pierini LM, Maxfield FR, Muller WA (2003) Targeted recycling of PECAM from endothelial surface-connected compartments during diapedesis. Nature 421:748–753CrossRefGoogle Scholar
  27. Mamdouh Z, Kreitzer GE, Muller WA (2008) Leukocyte transmigration requires kinesin-mediated microtubule-dependent membrane trafficking from the lateral border recycling compartment. J Exp Med 205:951–966CrossRefGoogle Scholar
  28. Mandicourt G, Iden S, Ebnet K, Aurrand-Lions M, Imhof BA (2007) JAM-C regulates tight junctions and integrin-mediated cell adhesion and migration. J Biol Chem 282:1830–1837CrossRefGoogle Scholar
  29. Maslin CL, Kedzierska K, Webster NL, Muller WA, Crowe SM (2005) Transendothelial migration of monocytes: the underlying molecular mechanisms and consequences of HIV-1 infection. Curr HIV Res 3:303–317CrossRefGoogle Scholar
  30. Matsutani T, Tanaka T, Tohya K, Otani K, Jang MH, Umemoto E, Taniguchi K, Hayasaka H, Ueda K, Miyasaka M (2007) Plasmacytoid dendritic cells employ multiple cell adhesion molecules sequentially to interact with high endothelial venule cells–molecular basis of their trafficking to lymph nodes. Int Immunol 19:1031–1037CrossRefGoogle Scholar
  31. Moog-Lutz C, Cave-Riant F, Guibal FC, Breau MA, Di Gioia Y, Couraud PO, Cayre YE, Bourdoulous S, Lutz PG (2003) JAML, a novel protein with characteristics of a junctional adhesion molecule, is induced during differentiation of myeloid leukemia cells. Blood 102:3371–3378CrossRefGoogle Scholar
  32. Morel PA, Turner MS (2010) Designing the optimal vaccine: the importance of cytokines and dendritic cells. Open Vaccine J 3:7–17CrossRefGoogle Scholar
  33. Muller WA (2003) Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol 24:327–334Google Scholar
  34. Muller WA (2007) PECAM: Regulating the start of diapedesis. In: Ley K (ed) Adhesion Molecules: Function and Inhibition. Birkhäuser Basel, Place, pp 201–220CrossRefGoogle Scholar
  35. Muller WA (2009) Mechanisms of transendothelial migration of leukocytes. Circ Res 105:223–230CrossRefGoogle Scholar
  36. Muller WA (2011) Mechanisms of leukocyte transendothelial migration. Annu Rev Pathol 6:323–344CrossRefGoogle Scholar
  37. Muller WA (2015) The regulation of transendothelial migration: new knowledge and new questions. Cardiovasc Res 107:310–320CrossRefGoogle Scholar
  38. Muller WA (2016) Transendothelial migration: unifying principles from the endothelial perspective. Immunol Rev 273:61–75CrossRefGoogle Scholar
  39. Nagamatsu G, Ohmura M, Mizukami T, Hamaguchi I, Hirabayashi S, Yoshida S, Hata Y, Suda T, Ohbo K (2006) A CTX family cell adhesion molecule, JAM4, is expressed in stem cell and progenitor cell populations of both male germ cell and hematopoietic cell lineages. Mol Cell Biol 26:8498–8506CrossRefGoogle Scholar
  40. Nathan C (2006) Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 6:173–182CrossRefGoogle Scholar
  41. Palucka K, Banchereau J (2013) Dendritic-cell-based therapeutic cancer vaccines. Immunity 39:38–48CrossRefGoogle Scholar
  42. Parlato S, Santini SM, Lapenta C, Di Pucchio T, Logozzi M, Spada M, Giammarioli AM, Malorni W, Fais S, Belardelli F (2001) Expression of CCR-7, MIP-3beta, and Th-1 chemokines in type I IFN-induced monocyte-derived dendritic cells: importance for the rapid acquisition of potent migratory and functional activities. Blood 98:3022–3029CrossRefGoogle Scholar
  43. Pulendran B (2005) Variegation of the immune response with dendritic cells and pathogen recognition receptors. J Immunol 174:2457–2465CrossRefGoogle Scholar
  44. Roh SE, Jeong Y, Kang MH, Bae YS (2018) Junctional adhesion molecules mediate transendothelial migration of dendritic cell vaccine in cancer immunotherapy. Cancer Lett 434:196–205CrossRefGoogle Scholar
  45. Sallusto F, Schaerli P, Loetscher P, Schaniel C, Lenig D, Mackay CR, Qin S, Lanzavecchia A (1998) Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol 28:2760–2769CrossRefGoogle Scholar
  46. Schenkel AR, Mamdouh Z, Chen X, Liebman RM, Muller WA (2002) CD99 plays a major role in the migration of monocytes through endothelial junctions. Nat Immunol 3:143–150CrossRefGoogle Scholar
  47. Schenkel AR, Mamdouh Z, Muller WA (2004) Locomotion of monocytes on endothelium is a critical step during extravasation. Nat Immunol 5:393–400CrossRefGoogle Scholar
  48. Schimmel L, Heemskerk N, Van Buul JD (2017) Leukocyte transendothelial migration: A local affair. Small GTPases 8:1–15CrossRefGoogle Scholar
  49. Steinman RM, Banchereau J (2007) Taking dendritic cells into medicine. Nature 449:419–426CrossRefGoogle Scholar
  50. Steinman RM, Dhodapkar M (2001) Active immunization against cancer with dendritic cells: the near future. Int J Cancer 94:459–473CrossRefGoogle Scholar
  51. Tacken PJ, De Vries IJ, Torensma R, Figdor CG (2007) Dendritic-cell immunotherapy: from ex vivo loading to in vivo targeting. Nat Rev Immunol 7:790–802CrossRefGoogle Scholar
  52. Takayama T, Morelli AE, Onai N, Hirao M, Matsushima K, Tahara H, Thomson AW (2001) Mammalian and viral IL-10 enhance C-C chemokine receptor 5 but down-regulate C-C chemokine receptor 7 expression by myeloid dendritic cells: impact on chemotactic responses and in vivo homing ability. J Immunol 166:7136–7143CrossRefGoogle Scholar
  53. Verdijk P, Aarntzen EH, Punt CJ, De Vries IJ, Figdor CG (2008) Maximizing dendritic cell migration in cancer immunotherapy. Expert Opin Biol Ther 8:865–874CrossRefGoogle Scholar
  54. Verdino P, Witherden DA, Havran WL, Wilson IA (2010) The molecular interaction of CAR and JAML recruits the central cell signal transducer PI3K. Science 329:1210–1214CrossRefGoogle Scholar
  55. Weber C, Fraemohs L, Dejana E (2007) The role of junctional adhesion molecules in vascular inflammation. Nat Rev Immunol 7:467–477CrossRefGoogle Scholar
  56. Weis M, Schlichting CL, Engleman EG, Cooke JP (2002) Endothelial determinants of dendritic cell adhesion and migration: new implications for vascular diseases. Arterioscler Thromb Vasc Biol 22:1817–1823CrossRefGoogle Scholar
  57. Xu H, Guan H, Zu G, Bullard D, Hanson J, Slater M, Elmets CA (2001) The role of ICAM-1 molecule in the migration of Langerhans cells in the skin and regional lymph node. Eur J Immunol 31:3085–3093CrossRefGoogle Scholar
  58. Yanagihara S, Komura E, Nagafune J, Watarai H, Yamaguchi Y (1998) EBI1/CCR58 is a new member of dendritic cell chemokine receptor that is up-regulated upon maturation. J Immunol 161:3096–3102Google Scholar
  59. Yonekawa K, Harlan JM (2005) Targeting leukocyte integrins in human diseases. J Leukoc Biol 77:129–140CrossRefGoogle Scholar
  60. Zen K, Liu Y, Mccall IC, Wu T, Lee W, Babbin BA, Nusrat A, Parkos CA (2005) Neutrophil migration across tight junctions is mediated by adhesive interactions between epithelial coxsackie and adenovirus receptor and a junctional adhesion molecule-like protein on neutrophils. Mol Biol Cell 16:2694–2703CrossRefGoogle Scholar
  61. Zernecke A, Liehn EA, Fraemohs L, Von Hundelshausen P, Koenen RR, Corada M, Dejana E, Weber C (2006) Importance of junctional adhesion molecule-A for neointimal lesion formation and infiltration in atherosclerosis-prone mice. Arterioscler Thromb Vasc Biol 26:e10–13CrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  1. 1.Department of Biological SciencesScience Research Center (SRC) for Immune Research on Non-lymphoid Organ (CIRNO), Sungkyunkwan UniversitySuwonSouth Korea
  2. 2.Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of Biological Science, Research Complex Bldg 1Sungkyunkwan UniversitySuwonSouth Korea

Personalised recommendations