Abstract
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.
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Vieweg J, Su Z, Dahm P, Kusmartsev S. Reversal of tumor-mediated immunosuppression. Clin Cancer Res. 2007;13(2 Pt 2):727s–32s.
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.
Wang RF. Functional control of regulatory T cells and cancer immunotherapy. Semin Cancer Biol. 2006;16(2):106–14.
Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6(4):295–307.
Linehan DC, Goedegebuure PS. CD25+ CD4+ regulatory T-cells in cancer. Immunol Res. 2005;32(1–3):155–68.
Wang HY, Wang RF. Antigen-specific CD4+ regulatory T cells in cancer: implications for immunotherapy. Microbes Infect. 2005;7(7–8):1056–62.
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.
Villadangos JA, Schnorrer P. Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat Rev Immunol. 2007;7(7):543–55.
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.
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.
Zamanakou M, Germenis AE, Karanikas V. Tumor immune escape mediated by indoleamine 2, 3-dioxygenase. Immunol Lett. 2007;111(2):69–75.
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.
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.
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.
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.
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.
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.
Popov A, Schultze JL. IDO-expressing regulatory dendritic cells in cancer and chronic infection. J Mol Med. 2008;86(2):145–60.
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.
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.
Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–61.
Cui W, Taub DD, Gardner K. qPrimerDepot: a primer database for quantitative real time PCR. Nucleic Acids Res. 2007;35(Database issue):805–9.
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.
Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101–8.
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.
Motamedi M, Hadjati J. Effect of Listeria monocytogenes on tumor immunotherapy with dendritic cells. Yakhteh Med J. 2007;8(4):252–7.
Morse MA, Hall JR, Plate JM. Countering tumor-induced immunosuppression during immunotherapy for pancreatic cancer. Expert Opin Biol Ther. 2009;9(3):331–9.
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.
Katz JB, Muller AJ, Prendergast GC. Indoleamine 2, 3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev. 2008;222:206–21.
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.
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This research has been supported by Tehran University of Medical Sciences and Health Services (Grant number: 86-03-30-6154).
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Samadi-Foroushani, M., Vahabpour, R., Memarnejadian, A. et al. Immune responses regulation following antitumor dendritic cell-based prophylactic, concurrent, and therapeutic vaccination. Med Oncol 28 (Suppl 1), 660–666 (2011). https://doi.org/10.1007/s12032-010-9720-z
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DOI: https://doi.org/10.1007/s12032-010-9720-z