Medical Oncology

, Volume 28, Supplement 1, pp 660–666 | Cite as

Immune responses regulation following antitumor dendritic cell-based prophylactic, concurrent, and therapeutic vaccination

  • Morteza Samadi-Foroushani
  • Rouhollah Vahabpour
  • Arash Memarnejadian
  • Afshin Namdar
  • Masoumeh Khamisabadi
  • Seyed Mehdi Sadat
  • Hossein Asgarian-Omran
  • Kayhan Azadmanesh
  • Parviz Kokhaei
  • Mohammad Reza Aghasadeghi
  • Jamshid HadjatiEmail author
Original Paper


There is ample evidence in favor of various immunosuppressive mechanisms that weaken antitumor immune responses and affect currently used immunotherapies. Induction of regulatory T cells (Treg) and secretion of indoleamine 2,3-dioxygenase (IDO) by tumor tissue are considered as two main mechanisms of tumor immune escape. However, little is known about the contribution of these mechanisms on the modulation of dendritic cell vaccine-mediated antitumor response. To address this concern, we assessed Treg’s infiltration and the expression of Foxp3 and IDO genes in tumor microenvironment following dendritic cell-based antitumor immunotherapy of mice in different protocols of prophylactic, concurrent, and therapeutic vaccination. According to cytotoxicity assay, the vaccinated mice exposed efficient induction of splenic CTLs in all groups. However, only the mice immunized in prophylactic regimen significantly retarded the growth of tumor cells. Interestingly, the Treg content of tumor samples and transcriptional level of both Foxp3 and IDO genes were reduced in this group, while animals that received the vaccine in concurrent and therapeutic protocols showed increase in tumor-infiltrating Tregs and mRNA levels of Foxp3 and IDO. Accordingly, higher expression of these genes resulted in more inhibition of antitumor response. Our findings indicate that tumor progression may enhance the immunoregulatory response and hence emphasize to the effectiveness of vaccination in early stages of tumor growth for avoiding induction of such regulatory responses.


Dendritic cell Regulatory T cell Foxp3 IDO Tumor immunotherapy 



This research has been supported by Tehran University of Medical Sciences and Health Services (Grant number: 86-03-30-6154).

Conflict of interest

Authors have no actual or potential conflict of interest.


  1. 1.
    Vieweg J, Su Z, Dahm P, Kusmartsev S. Reversal of tumor-mediated immunosuppression. Clin Cancer Res. 2007;13(2 Pt 2):727s–32s.PubMedCrossRefGoogle Scholar
  2. 2.
    Rabinovich GA, Gabrilovich D, Sotomayor EM, Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007;25:267–96.PubMedCrossRefGoogle Scholar
  3. 3.
    Wang RF. Functional control of regulatory T cells and cancer immunotherapy. Semin Cancer Biol. 2006;16(2):106–14.PubMedCrossRefGoogle Scholar
  4. 4.
    Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6(4):295–307.PubMedCrossRefGoogle Scholar
  5. 5.
    Linehan DC, Goedegebuure PS. CD25+ CD4+ regulatory T-cells in cancer. Immunol Res. 2005;32(1–3):155–68.PubMedCrossRefGoogle Scholar
  6. 6.
    Wang HY, Wang RF. Antigen-specific CD4+ regulatory T cells in cancer: implications for immunotherapy. Microbes Infect. 2005;7(7–8):1056–62.PubMedCrossRefGoogle Scholar
  7. 7.
    Banerjee DK, Dhodapkar MV, Matayeva E, Steinman RM, Dhodapkar KM. Expansion of FOXP3high regulatory T cells by human dendritic cells (DCs) in vitro and after injection of cytokine-matured DCs in myeloma patients. Blood. 2006;108(8):2655–61.PubMedCrossRefGoogle Scholar
  8. 8.
    Villadangos JA, Schnorrer P. Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat Rev Immunol. 2007;7(7):543–55.PubMedCrossRefGoogle Scholar
  9. 9.
    Ouabed A, Hubert FX, Chabannes D, Gautreau L, Heslan M, Josien R. Differential control of T regulatory cell proliferation and suppressive activity by mature plasmacytoid versus conventional spleen dendritic cells. J Immunol. 2008;180(9):5862–70.PubMedGoogle Scholar
  10. 10.
    Yates SF, Paterson AM, Nolan KF, Cobbold SP, Saunders NJ, Waldmann H, et al. Induction of regulatory T cells and dominant tolerance by dendritic cells incapable of full activation. J Immunol. 2007;179(2):967–76.PubMedGoogle Scholar
  11. 11.
    Zamanakou M, Germenis AE, Karanikas V. Tumor immune escape mediated by indoleamine 2, 3-dioxygenase. Immunol Lett. 2007;111(2):69–75.PubMedCrossRefGoogle Scholar
  12. 12.
    Curti A, Trabanelli S, Salvestrini V, Baccarani M, Lemoli RM. The role of indoleamine 2, 3-dioxygenase in the induction of immune tolerance: focus on hematology. Blood. 2009;113(11):2394–401.PubMedCrossRefGoogle Scholar
  13. 13.
    Wobser M, Voigt H, Houben R, Eggert AO, Freiwald M, Kaemmerer U, et al. Dendritic cell based antitumor vaccination: impact of functional indoleamine 2, 3-dioxygenase expression. Cancer Immunol Immunother. 2007;56(7):1017–24.PubMedCrossRefGoogle Scholar
  14. 14.
    von Bergwelt-Baildon MS, Popov A, Saric T, Chemnitz J, Classen S, Stoffel MS, et al. CD25 and indoleamine 2, 3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition. Blood. 2006;108(1):228–37.CrossRefGoogle Scholar
  15. 15.
    Braun D, Longman RS, Albert ML. A two-step induction of indoleamine 2, 3 dioxygenase (IDO) activity during dendritic-cell maturation. Blood. 2005;106(7):2375–81.PubMedCrossRefGoogle Scholar
  16. 16.
    Puccetti P, Grohmann U. IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-kappaB activation. Nat Rev Immunol. 2007;7(10):817–23.PubMedCrossRefGoogle Scholar
  17. 17.
    Sharma MD, Hou D-Y, Liu Y, Koni PA, Metz R, Chandler P, Mellor AL, He Y, Munn DH. Indoleamine 2, 3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood. 2009;113(24):6102–11.PubMedCrossRefGoogle Scholar
  18. 18.
    Popov A, Schultze JL. IDO-expressing regulatory dendritic cells in cancer and chronic infection. J Mol Med. 2008;86(2):145–60.PubMedCrossRefGoogle Scholar
  19. 19.
    Khamisabadi M, Arab S, Motamedi M, Khansari N, Moazzeni SM, Gheflati Z, et al. Listeria monocytogenes activated dendritic cell based vaccine for prevention of experimental tumor in mice. Iran J Immunol. 2008;5(1):36–44.PubMedGoogle Scholar
  20. 20.
    Inaba K, Inaba M, Romani N, Aya H, Deguchi M, Ikehara S, et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med. 1992;176(6):1693–702.PubMedCrossRefGoogle Scholar
  21. 21.
    Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–61.PubMedCrossRefGoogle Scholar
  22. 22.
    Cui W, Taub DD, Gardner K. qPrimerDepot: a primer database for quantitative real time PCR. Nucleic Acids Res. 2007;35(Database issue):805–9.CrossRefGoogle Scholar
  23. 23.
    Hansen AM, Ball HJ, Mitchell AJ, Miu J, Takikawa O, Hunt NH. Increased expression of indoleamine 2, 3-dioxygenase in murine malaria infection is predominantly localised to the vascular endothelium. Int J Parasitol. 2004;34(12):1309–19.PubMedCrossRefGoogle Scholar
  24. 24.
    Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Lizee G, Radvanyi LG, Overwijk WW, Hwu P. Improving antitumor immune responses by circumventing immunoregulatory cells and mechanisms. Clin Cancer Res. 2006;12(16):4794–803.PubMedCrossRefGoogle Scholar
  26. 26.
    Motamedi M, Hadjati J. Effect of Listeria monocytogenes on tumor immunotherapy with dendritic cells. Yakhteh Med J. 2007;8(4):252–7.Google Scholar
  27. 27.
    Morse MA, Hall JR, Plate JM. Countering tumor-induced immunosuppression during immunotherapy for pancreatic cancer. Expert Opin Biol Ther. 2009;9(3):331–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Norian LA, Rodriguez PC, O’Mara LA, Zabaleta J, Ochoa AC, Cella M, et al. Tumor-infiltrating regulatory dendritic cells inhibit CD8+ T cell function via L-arginine metabolism. Cancer Res. 2009;69(7):3086–94.PubMedCrossRefGoogle Scholar
  29. 29.
    Katz JB, Muller AJ, Prendergast GC. Indoleamine 2, 3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev. 2008;222:206–21.PubMedCrossRefGoogle Scholar
  30. 30.
    Basu GD, Tinder TL, Bradley JM, Tu T, Hattrup CL, Pockaj BA, et al. Cyclooxygenase-2 inhibitor enhances the efficacy of a breast cancer vaccine: role of IDO. J Immunol. 2006;177(4):2391–402.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Morteza Samadi-Foroushani
    • 1
  • Rouhollah Vahabpour
    • 2
  • Arash Memarnejadian
    • 2
  • Afshin Namdar
    • 1
  • Masoumeh Khamisabadi
    • 1
  • Seyed Mehdi Sadat
    • 2
  • Hossein Asgarian-Omran
    • 1
  • Kayhan Azadmanesh
    • 2
  • Parviz Kokhaei
    • 3
    • 4
  • Mohammad Reza Aghasadeghi
    • 2
  • Jamshid Hadjati
    • 1
    Email author
  1. 1.Department of Immunology, School of MedicineTehran University of Medical SciencesTehranIran
  2. 2.Pasteur Institute of IranTehranIran
  3. 3.Department of ImmunologySemnan University of Medical SciencesSemnanIran
  4. 4.Immune and Gene Therapy Lab. CCKKarolinska University HospitalSolna, StockholmSweden

Personalised recommendations