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Deoxypodophyllotoxin Induces a Th1 Response and Enhances the Antitumor Efficacy of a Dendritic Cell-based Vaccine

  • Lee, Jun-Sik (Department of Biology, College of Natural Sciences, Chosun University) ;
  • Kim, Dae-Hyun (Rangos Research Center, Children's Hospital of Pittsburgh, Department of Pediatrics, University of Pittsburgh School of Medicine) ;
  • Lee, Chang-Min (Department of Microbiology and Immunology, School of Medicine, Pusan National University) ;
  • Ha, Tae-Kwun (Department of Surgery, Busan Paik Hospital, Inje University, College of Medicine) ;
  • Noh, Kyung-Tae (Department of Microbiology and Immunology, School of Medicine, Pusan National University) ;
  • Park, Jin-Wook (Department of Microbiology and Immunology, School of Medicine, Pusan National University) ;
  • Heo, Deok-Rim (Department of Microbiology and Immunology, School of Medicine, Pusan National University) ;
  • Son, Kwang-Hee (Department of Microbiology and Immunology, School of Medicine, Pusan National University) ;
  • Jung, In-Duk (Department of Microbiology and Immunology, School of Medicine, Pusan National University) ;
  • Lee, Eun-Kyung (Yongsan Hospital College of Medicine Chung-Ang University) ;
  • Shin, Yong-Kyoo (Department of Pharmacology, College of Medicine, Chung-Ang University) ;
  • Ahn, Soon-Cheol (Department of Microbiology and Immunology, School of Medicine, Pusan National University) ;
  • Park, Yeong-Min (Department of Microbiology and Immunology, School of Medicine, Pusan National University)
  • Received : 2011.01.21
  • Accepted : 2011.02.11
  • Published : 2011.02.28
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Abstract

Background: Dendritic cell (DC)-based vaccines are currently being evaluated as a novel strategy for tumor vaccination and immunotherapy. However, inducing long-term regression in established tumor-implanted mice is difficult. Here, we show that deoxypohophyllotoxin (DPT) induces maturation and activation of bone marrow-derived DCs via Toll-like receptor (TLR) 4 activation of MAPK and NF-${\kappa}B$. Methods: The phenotypic and functional maturation of DPT-treated DCs was assessed by flow cytometric analysis and cytokine production, respectively. DPT-treated DCs was also used for mixed leukocyte reaction to evaluate T cell-priming capacity and for tumor regression against melanoma. Results: DPT promoted the activation of $CD8^+$ T cells and the Th1 immune response by inducing IL-12 production in DCs. In a B16F10 melanoma-implanted mouse model, we demonstrated that DPT-treated DCs (DPT-DCs) enhance immune priming and regression of an established tumor in vivo. Furthermore, migration of DPT-DCs to the draining lymph nodes was induced via CCR7 upregulation. Mice that received DPT-DCs displayed enhanced antitumor therapeutic efficacy, which was associated with increased IFN-${\gamma}$ production and induction of cytotoxic T lymphocyte activity. Conclusion: These findings strongly suggest that the adjuvant effect of DPT in DC vaccination is associated with the polarization of T effector cells toward a Th1 phenotype and provides a potential therapeutic antitumor immunity.

Keywords

References

  1. Tobiasova Z, Pospisilova D, Miller AM, Minarik I, Sochorova K, Spisek R, Rob L, Bartunkova J: In vitro assessment of dendritic cells pulsed with apoptotic tumor cells as a vaccine for ovarian cancer patients. Clin Immunol 122;18-27, 2007 https://doi.org/10.1016/j.clim.2006.09.003
  2. Bennett SR, Carbone FR, Karamalis F, Miller JF, Heath WR: Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help. J Exp Med 186;65-70, 1997 https://doi.org/10.1084/jem.186.1.65
  3. Steinman RM: The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 9;271-296, 1991 https://doi.org/10.1146/annurev.iy.09.040191.001415
  4. Morisaki T, Matsumoto K, Onishi H, Kuroki H, Baba E, Tasaki A, Kubo M, Nakamura M, Inaba S, Yamaguchi K, Tanaka M, Katano M: Dendritic cell-based combined immunotherapy with autologous tumor-pulsed dendritic cell vaccine and activated T cells for cancer patients: rationale, current progress, and perspectives. Hum Cell 16;175-182, 2003 https://doi.org/10.1111/j.1749-0774.2003.tb00151.x
  5. Rock KL, Clark K. Analysis of the role of MHC class II presentation in the stimulation of cytotoxic T lymphocytes by antigens targeted into the exogenous antigen-MHC class I presentation pathway. J Immunol 156;3721-3726, 1996
  6. Salio M, Cerundolo V, Lanzavecchia A: Dendritic cell maturation is induced by mycoplasma infection but not by necrotic cells. Eur J Immunol 30;705-708, 2000 https://doi.org/10.1002/1521-4141(200002)30:2<705::AID-IMMU705>3.0.CO;2-P
  7. Shimizu K, Thomas EK, Giedlin M, Mule JJ: Enhancement of tumor lysate- and peptide-pulsed dendritic cell-based vaccines by the addition of foreign helper protein. Cancer Res 61;2618-2624, 2001
  8. Jeannin P, Renno T, Goetsch L, Miconnet I, Aubry JP, Delneste Y, Herbault N, Baussant T, Magistrelli G, Soulas C, Romero P, Cerottini JC, Bonnefoy JY: OmpA targets dendritic cells, induces their maturation and delivers antigen into the MHC class I presentation pathway. Nat Immunol 1;502-509, 2000 https://doi.org/10.1038/82751
  9. Sloan JM, Kershaw MH, Touloukian CE, Lapointe R, Robbins PF, Restifo NP, Hwu P: MHC class I and class II presentation of tumor antigen in retrovirally and adenovirally transduced dendritic cells. Cancer Gene Ther 9;946- 950, 2002 https://doi.org/10.1038/sj.cgt.7700509
  10. Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392;86-89, 1998 https://doi.org/10.1038/32183
  11. You Z, Hester J, Rollins L, Spagnoli GC, van der Bruggen P, Chen SY: A retrogen strategy for presentation of an intracellular tumor antigen as an exogenous antigen by dendritic cells induces potent antitumor T helper and CTL responses. Cancer Res 61;197-205, 2001
  12. Celluzzi CM, Mayordomo JI, Storkus WJ, Lotze MT, Falo LD Jr. Peptide-pulsed dendritic cells induce antigen-specific CTL-mediated protective tumor immunity. J Exp Med 183; 283-287, 1996 https://doi.org/10.1084/jem.183.1.283
  13. Huang J, Tatsumi T, Pizzoferrato E, Vujanovic N, Storkus WJ: Nitric oxide sensitizes tumor cells to dendritic cellmediated apoptosis, uptake, and cross-presentation. Cancer Res 65;8461-8470, 2005 https://doi.org/10.1158/0008-5472.CAN-05-0654
  14. Liu Y, Bi X, Xu S, Xiang J: Tumor-infiltrating dendritic cell subsets of progressive or regressive tumors induce suppressive or protective immune responses. Cancer Res 65; 4955-4962, 2005 https://doi.org/10.1158/0008-5472.CAN-04-3957
  15. Jarnicki AG, Conroy H, Brereton C, Donnelly G, Toomey D, Walsh K, Sweeney C, Leavy O, Fletcher J, Lavelle EC, Dunne P, Mills KH: Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics. J Immunol 180; 3797-3806, 2008 https://doi.org/10.4049/jimmunol.180.6.3797
  16. Zanoni I, Foti M, Ricciardi-Castagnoli P, Granucci F: TLR-dependent activation stimuli associated with Th1 responses confer NK cell stimulatory capacity to mouse dendritic cells. J Immunol 175;286-292, 2005 https://doi.org/10.4049/jimmunol.175.1.286
  17. Kane CM, Cervi L, Sun J, McKee AS, Masek KS, Shapira S, Hunter CA, Pearce EJ: Helminth antigens modulate TLR-initiated dendritic cell activation. J Immunol 173;7454- 7461, 2004 https://doi.org/10.4049/jimmunol.173.12.7454
  18. Krieg AM: Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 5;471-484, 2006 https://doi.org/10.1038/nrd2059
  19. Chan CW, Crafton E, Fan HN, Flook J, Yoshimura K, Skarica M, Brockstedt D, Dubensky TW, Stins MF, Lanier LL, Pardoll DM, Housseau F: Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity. Nat Med 12;207-213, 2006 https://doi.org/10.1038/nm1352
  20. Kapsenberg ML: Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 3;984-993, 2003 https://doi.org/10.1038/nri1246
  21. Lee JS, Lee JC, Lee CM, Jung ID, Jeong YI, Seong EY, Chung HY, Park YM: Outer membrane protein A of Acinetobacter baumannii induces differentiation of CD4＋ T cells toward a Th1 polarizing phenotype through the activation of dendritic cells. Biochem Pharmacol 74;86-97, 2007 https://doi.org/10.1016/j.bcp.2007.02.012
  22. Sivori S, Falco M, Della Chiesa M, Carlomagno S, Vitale M, Moretta L, Moretta A: CpG and double-stranded RNA trigger human NK cells by Toll-like receptors: induction of cytokine release and cytotoxicity against tumors and dendritic cells. Proc Natl Acad Sci U S A 101;10116-10121, 2004 https://doi.org/10.1073/pnas.0403744101
  23. Kim Y, Kim SB, You YJ, Ahn BZ: Deoxypodophyllotoxin; the cytotoxic and antiangiogenic component from Pulsatilla koreana. Planta Med 68;271-274, 2002 https://doi.org/10.1055/s-2002-23140
  24. Sudo K, Konno K, Shigeta S, Yokota T: Inhibitory effects of podophyllotoxin derivatives on herpes simplex virus replication. Antivir Chem Chemother 9;263-267, 1998 https://doi.org/10.1177/095632029800900307
  25. Jin M, Moon TC, Quan Z, Lee E, Kim YK, Yang JH, Suh SJ, Jeong TC, Lee SH, Kim CH, Chang HW: The naturally occurring flavolignan, deoxypodophyllotoxin, inhibits lipopolysaccharide- induced iNOS expression through the NF-kappaB activation in RAW264.7 macrophage cells. Biol Pharm Bull 31;1312-1315, 2008 https://doi.org/10.1248/bpb.31.1312
  26. Lyons AB: Analysing cell division in vivo and in vitro using flow cytometric measurement of CFSE dye dilution. J Immunol Methods 243;147-154, 2000 https://doi.org/10.1016/S0022-1759(00)00231-3
  27. Preville X, Ladant D, Timmerman B, Leclerc C: Eradication of established tumors by vaccination with recombinant Bordetella pertussis adenylate cyclase carrying the human papillomavirus 16 E7 oncoprotein. Cancer Res 65;641-649, 2005
  28. Abe M, Zahorchak AF, Colvin BL, Thomson AW: Migratory responses of murine hepatic myeloid, lymphoid-related, and plasmacytoid dendritic cells to CC chemokines. Transplantation 78;762-765, 2004 https://doi.org/10.1097/01.TP.0000130450.61215.3B
  29. Mosca PJ, Hobeika AC, Clay TM, Nair SK, Thomas EK, Morse MA, Lyerly HK: A subset of human monocyte- derived dendritic cells expresses high levels of interleukin- 12 in response to combined CD40 ligand and interferon- gamma treatment. Blood 96;3499-3504, 2000
  30. Langenkamp A, Messi M, Lanzavecchia A, Sallusto F: Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nat Immunol 1;311- 316, 2000 https://doi.org/10.1038/79758
  31. Trinchieri G: Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol 13;251-276, 1995 https://doi.org/10.1146/annurev.iy.13.040195.001343
  32. Lutz MB, Assmann CU, Girolomoni G, Ricciardi-Castagnoli P: Different cytokines regulate antigen uptake and presentation of a precursor dendritic cell line. Eur J Immunol 26;586-594, 1996 https://doi.org/10.1002/eji.1830260313
  33. An H, Yu Y, Zhang M, Xu H, Qi R, Yan X, Liu S, Wang W, Guo Z, Guo J, Qin Z, Cao X: Involvement of ERK, p38 and NF-kappaB signal transduction in regulation of TLR2, TLR4 and TLR9 gene expression induced by lipopolysaccharide in mouse dendritic cells. Immunology 106;38-45, 2002 https://doi.org/10.1046/j.1365-2567.2002.01401.x
  34. MacDonald KP, Kuns RD, Rowe V, Morris ES, Banovic T, Bofinger H, O'Sullivan B, Markey KA, Don AL, Thomas R, Hill GR: Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD. Blood 109;5049-5057, 2007 https://doi.org/10.1182/blood-2007-01-067249
  35. Sioud M, Fløisand Y: TLR agonists induce the differentiation of human bone marrow CD34+ progenitors into CD11c+ CD80/86+ DC capable of inducing a Th1-type response. Eur J Immunol 37;2834-2846, 2007 https://doi.org/10.1002/eji.200737112
  36. Sweet CR, Conlon J, Golenbock DT, Goguen J, Silverman N: YopJ targets TRAF proteins to inhibit TLR-mediated NF-kappaB, MAPK and IRF3 signal transduction. Cell Microbiol 9;2700-2715, 2007 https://doi.org/10.1111/j.1462-5822.2007.00990.x
  37. Guiducci C, Ghirelli C, Marloie-Provost MA, Matray T, Coffman RL, Liu YJ, Barrat FJ, Soumelis V: PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation. J Exp Med 205;315-322, 2008 https://doi.org/10.1084/jem.20070763
  38. Ato M, Stager S, Engwerda CR, Kaye PM: Defective CCR7 expression on dendritic cells contributes to the development of visceral leishmaniasis. Nat Immunol 3;1185-1191, Ato M, Stäger S, Engwerda CR, Kaye PM: Defective CCR7 expression on dendritic cells contributes to the development of visceral leishmaniasis. Nat Immunol 3;1185-1191, 2002 https://doi.org/10.1038/ni861
  39. Catusse J, Spinks J, Mattick C, Dyer A, Laing K, Fitzsimons C, Smit MJ, Gompels UA: Immunomodulation by herpesvirus U51A chemokine receptor via CCL5 and FOG-2 down-regulation plus XCR1 and CCR7 mimicry in human leukocytes. Eur J Immunol 38;763-777, 2008 https://doi.org/10.1002/eji.200737618
  40. Movassagh M, Spatz A, Davoust J, Lebecque S, Romero P, Pittet M, Rimoldi D, Lienard D, Gugerli O, Ferradini L, Robert C, Avril MF, Zitvogel L, Angevin E: 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, 2004 https://doi.org/10.1158/0008-5472.CAN-03-2969
  41. Sancho D, Mourao-Sa D, Joffre OP, Schulz O, Rogers NC, Pennington DJ, Carlyle JR, Reis e Sousa C: Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin. J Clin Invest 118;2098-2110, 2008 https://doi.org/10.1172/JCI34584
  42. Melief CJ: Cancer immunotherapy by dendritic cells. Immunity 29;372-383, 2008 https://doi.org/10.1016/j.immuni.2008.08.004
  43. Hatfield P, Merrick AE, West E, O'Donnell D, Selby P, Vile R, Melcher AA: Optimization of dendritic cell loading with tumor cell lysates for cancer immunotherapy. J Immunother 31;620-632, 2008 https://doi.org/10.1097/CJI.0b013e31818213df
  44. Okada N, Saito T, Masunaga Y, Tsukada Y, Nakagawa S, Mizuguchi H, Mori K, Okada Y, Fujita T, Hayakawa T, Mayumi T, Yamamoto A: Efficient antigen gene transduction using Arg-Gly-Asp fiber-mutant adenovirus vectors can potentiate antitumor vaccine efficacy and maturation of murine dendritic cells. Cancer Res 61;7913-7919, 2001
  45. Lee JS, Kim JW, Choi CH, Lee WK, Chung HY, Lee JC: Anti-tumor activity of Acinetobacter baumannii outer membrane protein A on dendritic cell-based immunotherapy against murine melanoma. J Microbiol 46;221-227, 2008 https://doi.org/10.1007/s12275-008-0052-z
  46. Usluoglu N, Pavlovic J, Moelling K, Radziwill G: RIP2 mediates LPS-induced p38 and IkappaBalpha signaling including IL-12 p40 expression in human monocyte-derived dendritic cells. Eur J Immunol 37;2317-2325, 2007 https://doi.org/10.1002/eji.200636388
  47. Kelsall BL, Stuber E, Neurath M, Strober W: Interleukin-12 production by dendritic cells. The role of CD40-CD40L interactions in Th1 T-cell responses. Ann N Y Acad Sci 795; 116-126, 1996 https://doi.org/10.1111/j.1749-6632.1996.tb52660.x
  48. Iwashita Y, Goto S, Tominaga M, Sasaki A, Ohmori N, Goto T, Sato S, Ohta M, Kitano S: Dendritic cell immunotherapy with poly (D,L-2,4-diaminobutyric acid)-mediated intratumoral delivery of the interleukin-12 gene suppresses tumor growth significantly. Cancer Sci 96;303-307, 2005 https://doi.org/10.1111/j.1349-7006.2005.00049.x
  49. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, Kano S, Honda K, Ohba Y, Mak TW, Taniguchi T: Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434;243-249, 2005 https://doi.org/10.1038/nature03308
  50. Ridge JP, Di Rosa F, Matzinger P: A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393:474-478, 1998 https://doi.org/10.1038/30989

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