Advertisement

Targeted Oncology

, Volume 7, Issue 1, pp 29–54 | Cite as

Targeting pattern recognition receptors in cancer immunotherapy

  • Nadège Goutagny
  • Yann Estornes
  • Uzma Hasan
  • Serge Lebecque
  • Christophe Caux
Review

Abstract

Pattern recognition receptors (PRRs) are known for many years for their role in the recognition of microbial products and the subsequent activation of the immune system. The 2011 Nobel Prize for medicine indeed rewarded J. Hoffmann/B. Beutler and R. Steinman for their revolutionary findings concerning the activation of the immune system, thus stressing the significance of understanding the mechanisms of activation of the innate immunity. Such immunostimulatory activities are of major interest in the context of cancer to induce long-term antitumoral responses. Ligands for the toll-like receptors (TLRs), a well-known family of PRR, have been shown to have antitumoral activities in several cancers. Those ligands are now undergoing extensive clinical investigations both as immunostimulant molecules and as adjuvant along with vaccines. However, when considering the use of these ligands in tumor therapy, one shall consider the potential effect on the tumor cells themselves as well as on the entire organism. Recent data indeed demonstrate that TLR activation in tumor cells could trigger both pro- or antitumoral effect depending on the context. This review discusses this balance between the intrinsic activation of PRR in tumor cells and the extrinsic microenvironment activation in term of overall effect of PRR ligands on tumor development. We review recent advances in the field and underline appealing prospects for clinical development of PRR agonists in the light of our current knowledge on their expression and activation.

Keywords

TLR RLR Cancer Immunotherapy Vaccine 

Notes

Conflict of interest

No funds were received in support of this study.

References

  1. 1.
    Dillman RO (2011) Cancer immunotherapy. Cancer Biother Radiopharm 26:1–64PubMedCrossRefGoogle Scholar
  2. 2.
    Coley WB (1991) The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop Relat Res 262:3–11PubMedGoogle Scholar
  3. 3.
    Goutagny N, Fitzgerald KA (2006) Pattern recognition receptors: an update. Expert Rev Clin Immunol 2:569–583PubMedCrossRefGoogle Scholar
  4. 4.
    Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801PubMedCrossRefGoogle Scholar
  5. 5.
    Barber GN (2011) Innate immune DNA sensing pathways: STING, AIMII and the regulation of interferon production and inflammatory responses. Curr Opin Immunol 23:10–20PubMedCrossRefGoogle Scholar
  6. 6.
    Barton GM, Kagan JC (2009) A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol 9:535–542PubMedCrossRefGoogle Scholar
  7. 7.
    Kono H, Rock KL (2008) How dying cells alert the immune system to danger. Nat Rev Immunol 8:279–289PubMedCrossRefGoogle Scholar
  8. 8.
    Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T et al (2002) Quantitative expression of toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 168:4531–4537PubMedGoogle Scholar
  9. 9.
    Zhang Z, Kim T, Bao M, Facchinetti V, Jung SY, Ghaffari AA et al (2011) DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. Immunity 34:866–878PubMedCrossRefGoogle Scholar
  10. 10.
    Ishikawa H, Ma Z, Barber GN (2009) STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461:788–792PubMedCrossRefGoogle Scholar
  11. 11.
    Bryant C, Fitzgerald KA (2009) Molecular mechanisms involved in inflammasome activation. Trends Cell Biol 19:455–464PubMedCrossRefGoogle Scholar
  12. 12.
    Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K et al (2005) Cell type-specific involvement of RIG-I in antiviral response. Immunity 23:19–28PubMedCrossRefGoogle Scholar
  13. 13.
    Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M et al (2004) The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5:730–737PubMedCrossRefGoogle Scholar
  14. 14.
    Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL et al (2008) Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9:847–856PubMedCrossRefGoogle Scholar
  15. 15.
    Kanneganti TD, Ozoren N, Body-Malapel M, Amer A, Park JH, Franchi L et al (2006) Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440:233–236PubMedCrossRefGoogle Scholar
  16. 16.
    Kanneganti TD, Body-Malapel M, Amer A, Park JH, Whitfield J, Franchi L et al (2006) Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J Biol Chem 281:36560–36568PubMedCrossRefGoogle Scholar
  17. 17.
    Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP et al (2004) Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430:213–218PubMedCrossRefGoogle Scholar
  18. 18.
    Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M et al (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228–232PubMedCrossRefGoogle Scholar
  19. 19.
    Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237–241PubMedCrossRefGoogle Scholar
  20. 20.
    Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES (2009) AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458:509–513PubMedCrossRefGoogle Scholar
  21. 21.
    Kim S, Bauernfeind F, Ablasser A, Hartmann G, Fitzgerald KA, Latz E et al (2010) Listeria monocytogenes is sensed by the NLRP3 and AIM2 inflammasome. Eur J Immunol 40:1545–1551PubMedCrossRefGoogle Scholar
  22. 22.
    Rathinam VA, Jiang Z, Waggoner SN, Sharma S, Cole LE, Waggoner L et al (2010) The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol 11:395–402PubMedCrossRefGoogle Scholar
  23. 23.
    Roberts TL, Idris A, Dunn JA, Kelly GM, Burnton CM, Hodgson S et al (2009) HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science 323:1057–1060PubMedCrossRefGoogle Scholar
  24. 24.
    Petrilli V, Dostert C, Muruve DA, Tschopp J (2007) The inflammasome: a danger sensing complex triggering innate immunity. Curr Opin Immunol 19:615–622PubMedCrossRefGoogle Scholar
  25. 25.
    Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–995PubMedCrossRefGoogle Scholar
  26. 26.
    Anderson KV, Bokla L, Nusslein-Volhard C (1985) Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell 42:791–798PubMedCrossRefGoogle Scholar
  27. 27.
    Hoffmann JA (2003) The immune response of Drosophila. Nature 426:33–38PubMedCrossRefGoogle Scholar
  28. 28.
    Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–397PubMedCrossRefGoogle Scholar
  29. 29.
    Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS et al (2005) TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308:1626–1629PubMedCrossRefGoogle Scholar
  30. 30.
    Zhang Z, Schluesener HJ (2006) Mammalian toll-like receptors: from endogenous ligands to tissue regeneration. Cell Mol Life Sci 63:2901–2907PubMedCrossRefGoogle Scholar
  31. 31.
    Hayashi F, Means TK, Luster AD (2003) Toll-like receptors stimulate human neutrophil function. Blood 102:2660–2669PubMedCrossRefGoogle Scholar
  32. 32.
    Muzio M, Bosisio D, Polentarutti N, D’Amico G, Stoppacciaro A, Mancinelli R et al (2000) Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol 164:5998–6004PubMedGoogle Scholar
  33. 33.
    Komiya A, Nagase H, Okugawa S, Ota Y, Suzukawa M, Kawakami A et al (2006) Expression and function of toll-like receptors in human basophils. Int Arch Allergy Immunol 140(Suppl 1):23–27PubMedCrossRefGoogle Scholar
  34. 34.
    Mansson A, Cardell LO (2009) Role of atopic status in Toll-like receptor (TLR)7- and TLR9-mediated activation of human eosinophils. J Leukoc Biol 85:719–727PubMedCrossRefGoogle Scholar
  35. 35.
    Genestier L, Taillardet M, Mondiere P, Gheit H, Bella C, Defrance T (2007) TLR agonists selectively promote terminal plasma cell differentiation of B cell subsets specialized in thymus-independent responses. J Immunol 178:7779–7786PubMedGoogle Scholar
  36. 36.
    Pan ZK, Fisher C, Li JD, Jiang Y, Huang S, Chen LY (2011) Bacterial LPS up-regulated TLR3 expression is critical for antiviral response in human monocytes: evidence for negative regulation by CYLD. Int Immunol 23:357–364PubMedCrossRefGoogle Scholar
  37. 37.
    Hasan UA, Trinchieri G, Vlach J (2005) Toll-like receptor signaling stimulates cell cycle entry and progression in fibroblasts. J Biol Chem 280:20620–20627PubMedCrossRefGoogle Scholar
  38. 38.
    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 31:3388–3393PubMedCrossRefGoogle Scholar
  39. 39.
    Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F et al (2001) Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 194:863–869PubMedCrossRefGoogle Scholar
  40. 40.
    Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, Visintin A, Latz E et al (2003) LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med 198:1043–1055PubMedCrossRefGoogle Scholar
  41. 41.
    Oshiumi H, Matsumoto M, Funami K, Akazawa T, Seya T (2003) TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction. Nat Immunol 4:161–167PubMedCrossRefGoogle Scholar
  42. 42.
    Honda K, Yanai H, Mizutani T, Negishi H, Shimada N, Suzuki N et al (2004) Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc Natl Acad Sci USA 101:15416–15421PubMedCrossRefGoogle Scholar
  43. 43.
    Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, Yamamoto M et al (2004) Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 5:1061–1068PubMedCrossRefGoogle Scholar
  44. 44.
    Hasan UA, Caux C, Perrot I, Doffin AC, Menetrier-Caux C, Trinchieri G et al (2007) Cell proliferation and survival induced by Toll-like receptors is antagonized by type I IFNs. Proc Natl Acad Sci USA 104:8047–8052PubMedCrossRefGoogle Scholar
  45. 45.
    Kollisch G, Kalali BN, Voelcker V, Wallich R, Behrendt H, Ring J et al (2005) Various members of the Toll-like receptor family contribute to the innate immune response of human epidermal keratinocytes. Immunology 114:531–541PubMedCrossRefGoogle Scholar
  46. 46.
    Gribar SC, Anand RJ, Sodhi CP, Hackam DJ (2008) The role of epithelial Toll-like receptor signaling in the pathogenesis of intestinal inflammation. J Leukoc Biol 83:493–498PubMedCrossRefGoogle Scholar
  47. 47.
    Grote K, Schuett H, Schieffer B (2011) Toll-like receptors in angiogenesis. Sci World J 11:981–991CrossRefGoogle Scholar
  48. 48.
    Hwa CH, Bae YC, Jung JS (2006) Role of toll-like receptors on human adipose-derived stromal cells. Stem Cells 24:2744–2752CrossRefGoogle Scholar
  49. 49.
    Bsibsi M, Ravid R, Gveric D, van Noort JM (2002) Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 61:1013–1021PubMedGoogle Scholar
  50. 50.
    Dupaul-Chicoine J, Yeretssian G, Doiron K, Bergstrom KS, McIntire CR, LeBlanc PM et al (2010) Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity 32:367–378PubMedCrossRefGoogle Scholar
  51. 51.
    Salcedo R, Worschech A, Cardone M, Jones Y, Gyulai Z, Dai RM et al (2010) MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J Exp Med 207:1625–1636PubMedCrossRefGoogle Scholar
  52. 52.
    Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118:229–241PubMedCrossRefGoogle Scholar
  53. 53.
    El-Omar EM, Ng MT, Hold GL (2008) Polymorphisms in Toll-like receptor genes and risk of cancer. Oncogene 27:244–252PubMedCrossRefGoogle Scholar
  54. 54.
    Huang B, Zhao J, Unkeless JC, Feng ZH, Xiong H (2008) TLR signaling by tumor and immune cells: a double-edged sword. Oncogene 27:218–224PubMedCrossRefGoogle Scholar
  55. 55.
    Merrell MA, Ilvesaro JM, Lehtonen N, Sorsa T, Gehrs B, Rosenthal E et al (2006) Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity. Mol Cancer Res 4:437–447PubMedCrossRefGoogle Scholar
  56. 56.
    Brignole C, Marimpietri D, Di PD, Perri P, Morandi F, Pastorino F et al (2010) Therapeutic targeting of TLR9 inhibits cell growth and induces apoptosis in neuroblastoma. Cancer Res 70:9816–9826PubMedCrossRefGoogle Scholar
  57. 57.
    Hasan UA, Bates E, Takeshita F, Biliato A, Accardi R, Bouvard V et al (2007) TLR9 expression and function is abolished by the cervical cancer-associated human papillomavirus type 16. J Immunol 178:3186–3197PubMedGoogle Scholar
  58. 58.
    Berger R, Fiegl H, Goebel G, Obexer P, Ausserlechner M, Doppler W et al (2010) Toll-like receptor 9 expression in breast and ovarian cancer is associated with poorly differentiated tumors. Cancer Sci 101:1059–1066PubMedCrossRefGoogle Scholar
  59. 59.
    Salaun B, Zitvogel L, Asselin-Paturel C, Morel Y, Chemin K, Dubois C et al (2011) TLR3 as a biomarker for the therapeutic efficacy of double-stranded RNA in breast cancer. Cancer Res 71:1607–1614PubMedCrossRefGoogle Scholar
  60. 60.
    Menendez D, Shatz M, Azzam K, Garantziotis S, Fessler MB, Resnick MA (2011) The Toll-like receptor gene family is integrated into human DNA damage and p53 networks. PLoS Genet 7:e1001360PubMedCrossRefGoogle Scholar
  61. 61.
    Kang DC, Gopalkrishnan RV, Wu Q, Jankowsky E, Pyle AM, Fisher PB (2002) mda-5: an interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties. Proc Natl Acad Sci USA 99:637–642PubMedCrossRefGoogle Scholar
  62. 62.
    Linder P (2006) Dead-box proteins: a family affair—active and passive players in RNP-remodeling. Nucleic Acids Res 34:4168–4180PubMedCrossRefGoogle Scholar
  63. 63.
    Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H et al (2005) IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6:981–988PubMedCrossRefGoogle Scholar
  64. 64.
    Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R et al (2005) Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167–1172PubMedCrossRefGoogle Scholar
  65. 65.
    Seth RB, Sun L, Ea CK, Chen ZJ (2005) Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122:669–682PubMedCrossRefGoogle Scholar
  66. 66.
    Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB (2005) VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 19:727–740PubMedCrossRefGoogle Scholar
  67. 67.
    Rothenfusser S, Goutagny N, DiPerna G, Gong M, Monks BG, Schoenemeyer A et al (2005) The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol 175:5260–5268PubMedGoogle Scholar
  68. 68.
    Satoh T, Kato H, Kumagai Y, Yoneyama M, Sato S, Matsushita K et al (2010) LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc Natl Acad Sci USA 107:1512–1517PubMedCrossRefGoogle Scholar
  69. 69.
    Venkataraman T, Valdes M, Elsby R, Kakuta S, Caceres G, Saijo S et al (2007) Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses. J Immunol 178:6444–6455PubMedGoogle Scholar
  70. 70.
    Pichlmair A, Schulz O, Tan CP, Naslund TI, Liljestrom P, Weber F et al (2006) RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314:997–1001PubMedCrossRefGoogle Scholar
  71. 71.
    Hornung V, Ellegast J, Kim S, Brzozka K, Jung A, Kato H et al (2006) 5′-Triphosphate RNA is the ligand for RIG-I. Science 314:994–997PubMedCrossRefGoogle Scholar
  72. 72.
    Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K et al (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105PubMedCrossRefGoogle Scholar
  73. 73.
    Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K et al (2008) Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med 205:1601–1610PubMedCrossRefGoogle Scholar
  74. 74.
    Zhang NN, Shen SH, Jiang LJ, Zhang W, Zhang HX, Sun YP et al (2008) RIG-I plays a critical role in negatively regulating granulocytic proliferation. Proc Natl Acad Sci USA 105:10553–10558PubMedCrossRefGoogle Scholar
  75. 75.
    Kim T, Pazhoor S, Bao M, Zhang Z, Hanabuchi S, Facchinetti V et al (2010) Aspartate-glutamate-alanine-histidine box motif (DEAH)/RNA helicase A helicases sense microbial DNA in human plasmacytoid dendritic cells. Proc Natl Acad Sci USA 107:15181–15186PubMedCrossRefGoogle Scholar
  76. 76.
    Jung A, Kato H, Kumagai Y, Kumar H, Kawai T, Takeuchi O et al (2008) Lymphocytoid choriomeningitis virus activates plasmacytoid dendritic cells and induces a cytotoxic T-cell response via MyD88. J Virol 82:196–206PubMedCrossRefGoogle Scholar
  77. 77.
    Hochrein H, Schlatter B, O’Keeffe M, Wagner C, Schmitz F, Schiemann M et al (2004) Herpes simplex virus type-1 induces IFN-alpha production via Toll-like receptor 9-dependent and -independent pathways. Proc Natl Acad Sci USA 101:11416–11421PubMedCrossRefGoogle Scholar
  78. 78.
    Hokeness-Antonelli KL, Crane MJ, Dragoi AM, Chu WM, Salazar-Mather TP (2007) IFN-alphabeta-mediated inflammatory responses and antiviral defense in liver is TLR9-independent but MyD88-dependent during murine cytomegalovirus infection. J Immunol 179:6176–6183PubMedGoogle Scholar
  79. 79.
    Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H et al (2003) Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301:640–643PubMedCrossRefGoogle Scholar
  80. 80.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732–738PubMedCrossRefGoogle Scholar
  81. 81.
    Yamamoto M, Sato S, Mori K, Hoshino K, Takeuchi O, Takeda K et al (2002) Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol 169:6668–6672PubMedGoogle Scholar
  82. 82.
    Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K et al (2005) Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol 175:2851–2858PubMedGoogle Scholar
  83. 83.
    Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964PubMedCrossRefGoogle Scholar
  84. 84.
    Balenga NA, Balenga NA (2007) Human TLR11 gene is repressed due to its probable interaction with profilin expressed in human. Med Hypotheses 68:456PubMedCrossRefGoogle Scholar
  85. 85.
    Haynes LM, Moore DD, Kurt-Jones EA, Finberg RW, Anderson LJ, Tripp RA (2001) Involvement of toll-like receptor 4 in innate immunity to respiratory syncytial virus. J Virol 75:10730–10737PubMedCrossRefGoogle Scholar
  86. 86.
    Kurt-Jones EA, Popova L, Kwinn L, Haynes LM, Jones LP, Tripp RA et al (2000) Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol 1:398–401PubMedCrossRefGoogle Scholar
  87. 87.
    Georgel P, Jiang Z, Kunz S, Janssen E, Mols J, Hoebe K et al (2007) Vesicular stomatitis virus glycoprotein G activates a specific antiviral Toll-like receptor 4-dependent pathway. Virology 362:304–313PubMedCrossRefGoogle Scholar
  88. 88.
    Rassa JC, Meyers JL, Zhang Y, Kudaravalli R, Ross SR (2002) Murine retroviruses activate B cells via interaction with toll-like receptor 4. Proc Natl Acad Sci USA 99:2281–2286PubMedCrossRefGoogle Scholar
  89. 89.
    Rolland A, Jouvin-Marche E, Viret C, Faure M, Perron H, Marche PN (2006) The envelope protein of a human endogenous retrovirus-W family activates innate immunity through CD14/TLR4 and promotes Th1-like responses. J Immunol 176:7636–7644PubMedGoogle Scholar
  90. 90.
    Cavaleiro R, Brunn GJ, Albuquerque AS, Victorino RM, Platt JL, Sousa AE (2007) Monocyte-mediated T cell suppression by HIV-2 envelope proteins. Eur J Immunol 37:3435–3444PubMedCrossRefGoogle Scholar
  91. 91.
    Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A et al (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050–1059PubMedCrossRefGoogle Scholar
  92. 92.
    Kagan JC, Su T, Horng T, Chow A, Akira S, Medzhitov R (2008) TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nat Immunol 9:361–368PubMedCrossRefGoogle Scholar
  93. 93.
    Lindstrom S, Hunter DJ, Gronberg H, Stattin P, Wiklund F, Xu J et al (2010) Sequence variants in the TLR4 and TLR6-1-10 genes and prostate cancer risk. Results based on pooled analysis from three independent studies. Cancer Epidemiol Biomarkers Prev 19:873–876PubMedCrossRefGoogle Scholar
  94. 94.
    Pimentel-Nunes P, Soares JB, Roncon-Albuquerque R Jr, Dinis-Ribeiro M, Leite-Moreira AF (2010) Toll-like receptors as therapeutic targets in gastrointestinal diseases. Expert Opin Ther Targets 14:347–368PubMedCrossRefGoogle Scholar
  95. 95.
    Kelly MG, Alvero AB, Chen R, Silasi DA, Abrahams VM, Chan S et al (2006) TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res 66:3859–3868PubMedCrossRefGoogle Scholar
  96. 96.
    Huang B, Zhao J, Li H, He KL, Chen Y, Chen SH et al (2005) Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res 65:5009–5014PubMedCrossRefGoogle Scholar
  97. 97.
    Szczepanski MJ, Czystowska M, Szajnik M, Harasymczuk M, Boyiadzis M, Kruk-Zagajewska A et al (2009) Triggering of Toll-like receptor 4 expressed on human head and neck squamous cell carcinoma promotes tumor development and protects the tumor from immune attack. Cancer Res 69:3105–3113PubMedCrossRefGoogle Scholar
  98. 98.
    Huang B, Zhao J, Shen S, Li H, He KL, Shen GX et al (2007) Listeria monocytogenes promotes tumor growth via tumor cell toll-like receptor 2 signaling. Cancer Res 67:4346–4352PubMedCrossRefGoogle Scholar
  99. 99.
    Cai Z, Sanchez A, Shi Z, Zhang T, Liu M, Zhang D (2011) Activation of Toll-like receptor 5 on breast cancer cells by flagellin suppresses cell proliferation and tumor growth. Cancer Res 71:2466–2475PubMedCrossRefGoogle Scholar
  100. 100.
    Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB et al (1991) A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional-cell carcinoma of the bladder. N Engl J Med 325:1205–1209PubMedCrossRefGoogle Scholar
  101. 101.
    Khanna OP, Son DL, Mazer H, Read J, Nugent D, Cottone R et al (1990) Multicenter study of superficial bladder cancer treated with intravesical bacillus Calmette-Guerin or adriamycin. Urology 35:101–108PubMedCrossRefGoogle Scholar
  102. 102.
    Shelley MD, Mason MD, Kynaston H (2010) Intravesical therapy for superficial bladder cancer: a systematic review of randomised trials and meta-analyses. Cancer Treat Rev 36:195–205PubMedCrossRefGoogle Scholar
  103. 103.
    Dovedi SJ, Davies BR (2009) Emerging targeted therapies for bladder cancer: a disease waiting for a drug. Cancer Metastasis Rev 28:355–367PubMedCrossRefGoogle Scholar
  104. 104.
    Alexandroff AB, Jackson AM, O’Donnell MA, James K (1999) BCG immunotherapy of bladder cancer: 20 years on. Lancet 353:1689–1694PubMedCrossRefGoogle Scholar
  105. 105.
    Ponticiello A, Perna F, Maione S, Stradolini M, Testa G, Terrazzano G et al (2004) Analysis of local T lymphocyte subsets upon stimulation with intravesical BCG: a model to study tuberculosis immunity. Respir Med 98:509–514PubMedCrossRefGoogle Scholar
  106. 106.
    Higuchi T, Shimizu M, Owaki A, Takahashi M, Shinya E, Nishimura T et al (2009) A possible mechanism of intravesical BCG therapy for human bladder carcinoma: involvement of innate effector cells for the inhibition of tumor growth. Cancer Immunol Immunother 58:1245–1255PubMedCrossRefGoogle Scholar
  107. 107.
    Tsuji S, Matsumoto M, Takeuchi O, Akira S, Azuma I, Hayashi A et al (2000) Maturation of human dendritic cells by cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guerin: involvement of toll-like receptors. Infect Immun 68:6883–6890PubMedCrossRefGoogle Scholar
  108. 108.
    von Meyenn F, Schaefer M, Weighardt H, Bauer S, Kirschning CJ, Wagner H et al (2006) Toll-like receptor 9 contributes to recognition of Mycobacterium bovis bacillus Calmette-Guerin by Flt3-ligand generated dendritic cells. Immunobiology 211:557–565CrossRefGoogle Scholar
  109. 109.
    Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL et al (2007) Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 13:54–61PubMedCrossRefGoogle Scholar
  110. 110.
    Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C et al (2009) Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 15:1170–1178PubMedCrossRefGoogle Scholar
  111. 111.
    Zitvogel L, Kepp O, Kroemer G (2011) Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 8:151–160PubMedCrossRefGoogle Scholar
  112. 112.
    Fucikova J, Kralikova P, Fialova A, Brtnicky T, Rob L, Bartunkova J et al (2011) Human tumor cells killed by anthracyclines induce a tumor-specific immune response. Cancer Res 71:4821–4833PubMedCrossRefGoogle Scholar
  113. 113.
    Giannini SL, Hanon E, Moris P, Van MM, Morel S, Dessy F et al (2006) Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine 24:5937–5949PubMedCrossRefGoogle Scholar
  114. 114.
    Didierlaurent AM, Morel S, Lockman L, Giannini SL, Bisteau M, Carlsen H et al (2009) AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J Immunol 183:6186–6197PubMedCrossRefGoogle Scholar
  115. 115.
    Cluff CW (2009) Monophosphoryl lipid A (PML) as an adjuvant for anti-cancer vaccines: clinical results. In: Jeannin JF (ed) Lipid A in cancer therapy. Landes Bioscience, AustinGoogle Scholar
  116. 116.
    Atanackovic D, Altorki NK, Stockert E, Williamson B, Jungbluth AA, Ritter E et al (2004) Vaccine-induced CD4+ T cell responses to MAGE-3 protein in lung cancer patients. J Immunol 172:3289–3296PubMedGoogle Scholar
  117. 117.
    Kruit WH (2008) Immunization with recombinant MAGE-A3 protein combined with adjuvant systems AS15 or AS02B in patients with unresectabke and progressive metastatic cutaneous melanoma: a randomized open-label phase II study of the EORTC Melanoma Group (16032-18031). J Clin Oncol 26:9065Google Scholar
  118. 118.
    Butts C, Maksymiuk A, Goss G, Soulieres D, Marshall E, Cormier Y et al (2011) Updated survival analysis in patients with stage IIIB or IV non-small-cell lung cancer receiving BLP25 liposome vaccine (L-BLP25): phase IIB randomized, multicenter, open-label trial. J Cancer Res Clin Oncol 137(9):1337–1342PubMedCrossRefGoogle Scholar
  119. 119.
    Miles DW, Towlson KE, Graham R, Reddish M, Longenecker BM, Taylor-Papadimitriou J et al (1996) A randomised phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment for the active specific immunotherapy of breast cancer. Br J Cancer 74:1292–1296PubMedCrossRefGoogle Scholar
  120. 120.
    Miles D, Roche H, Martin M, Perren TJ, Cameron DA, Glaspy J et al (2011) Phase III multicenter clinical trial of the sialyl-TN (STn)-keyhole limpet hemocyanin (KLH) vaccine for metastatic breast cancer. Oncologist 16(8):1092–1100PubMedCrossRefGoogle Scholar
  121. 121.
    Sharma P, Bajorin DF, Jungbluth AA, Herr H, Old LJ, Gnjatic S (2008) Immune responses detected in urothelial carcinoma patients after vaccination with NY-ESO-1 protein plus BCG and GM-CSF. J Immunother 31:849–857PubMedCrossRefGoogle Scholar
  122. 122.
    Vermorken JB, Claessen AM, van Tinteren H, Gall HE, Ezinga R, Meijer S et al (1999) Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial. Lancet 353:345–350PubMedCrossRefGoogle Scholar
  123. 123.
    Sarma PS, Shiu G, Neubauer RH, Baron S, Huebner RJ (1969) Virus-induced sarcoma of mice: inhibition by a synthetic polyribonucleotide complex. Proc Natl Acad Sci USA 62:1046–1051PubMedCrossRefGoogle Scholar
  124. 124.
    Levy HB, Law LW, Rabson AS (1969) Inhibition of tumor growth by polyinosinic-polycytidylic acid. Proc Natl Acad Sci USA 62:357–361PubMedCrossRefGoogle Scholar
  125. 125.
    Yu M, Lam J, Rada B, Leto TL, Levine SJ (2011) Double-stranded RNA induces shedding of the 34-kDa soluble TNFR1 from human airway epithelial cells via TLR3-TRIF-RIP1-dependent signaling: roles for dual oxidase 2- and caspase-dependent pathways. J Immunol 186:1180–1188PubMedCrossRefGoogle Scholar
  126. 126.
    Whitson JM, Noonan EJ, Pookot D, Place RF, Dahiya R (2009) Double stranded-RNA-mediated activation of P21 gene induced apoptosis and cell cycle arrest in renal cell carcinoma. Int J Cancer 125:446–452PubMedCrossRefGoogle Scholar
  127. 127.
    Weber A, Kirejczyk Z, Besch R, Potthoff S, Leverkus M, Hacker G (2010) Proapoptotic signalling through Toll-like receptor-3 involves TRIF-dependent activation of caspase-8 and is under the control of inhibitor of apoptosis proteins in melanoma cells. Cell Death Differ 17:942–951PubMedCrossRefGoogle Scholar
  128. 128.
    Taura M, Fukuda R, Suico MA, Eguma A, Koga T, Shuto T et al (2010) TLR3 induction by anticancer drugs potentiates poly I:C-induced tumor cell apoptosis. Cancer Sci 101:1610–1617PubMedCrossRefGoogle Scholar
  129. 129.
    Salaun B, Lebecque S, Matikainen S, Rimoldi D, Romero P (2007) Toll-like receptor 3 expressed by melanoma cells as a target for therapy? Clin Cancer Res 13:4565–4574PubMedCrossRefGoogle Scholar
  130. 130.
    Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T (2006) TLR3 can directly trigger apoptosis in human cancer cells. J Immunol 176:4894–4901PubMedGoogle Scholar
  131. 131.
    Paone A, Starace D, Galli R, Padula F, De CP, Filippini A et al (2008) Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis 29:1334–1342PubMedCrossRefGoogle Scholar
  132. 132.
    Morikawa T, Sugiyama A, Kume H, Ota S, Kashima T, Tomita K et al (2007) Identification of Toll-like receptor 3 as a potential therapeutic target in clear cell renal cell carcinoma. Clin Cancer Res 13:5703–5709PubMedCrossRefGoogle Scholar
  133. 133.
    Jiang Q, Wei H, Tian Z (2008) Poly I:C enhances cycloheximide-induced apoptosis of tumor cells through TLR3 pathway. BMC Cancer 8:12PubMedCrossRefGoogle Scholar
  134. 134.
    Friboulet L, Pioche-Durieu C, Rodriguez S, Valent A, Souquere S, Ripoche H et al (2008) Recurrent overexpression of c-IAP2 in EBV-associated nasopharyngeal carcinomas: critical role in resistance to Toll-like receptor 3-mediated apoptosis. Neoplasia 10:1183–1194PubMedGoogle Scholar
  135. 135.
    Friboulet L, Gourzones C, Tsao SW, Morel Y, Paturel C, Temam S et al (2010) Poly(I:C) induces intense expression of c-IAP2 and cooperates with an IAP inhibitor in induction of apoptosis in cancer cells. BMC Cancer 10:327PubMedCrossRefGoogle Scholar
  136. 136.
    Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M et al (2011) cIAPs block ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol Cell 43:449–463PubMedCrossRefGoogle Scholar
  137. 137.
    Chiron D, Pellat-Deceunynck C, Amiot M, Bataille R, Jego G (2009) TLR3 ligand induces NF-κB activation and various fates of multiple myeloma cells depending on IFN-κ production. J Immunol 182:4471–4478PubMedCrossRefGoogle Scholar
  138. 138.
    Pries R, Hogrefe L, Xie L, Frenzel H, Brocks C, Ditz C et al (2008) Induction of c-Myc-dependent cell proliferation through toll-like receptor 3 in head and neck cancer. Int J Mol Med 21:209–215PubMedGoogle Scholar
  139. 139.
    Wilson NS, Dixit V, Ashkenazi A (2009) Death receptor signal transducers: nodes of coordination in immune signaling networks. Nat Immunol 10:348–355PubMedCrossRefGoogle Scholar
  140. 140.
    Festjens N, Vanden Berghe T, Cornelis S, Vandenabeele P (2007) RIP1, a kinase on the crossroads of a cell’s decision to live or die. Cell Death Differ 14:400–410PubMedCrossRefGoogle Scholar
  141. 141.
    Tenev T, Bianchi K, Darding M, Broemer M, Langlais C, Wallberg F et al (2011) The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol Cell 43:432–448PubMedCrossRefGoogle Scholar
  142. 142.
    Grossman SA, Ye X, Piantadosi S, Desideri S, Nabors LB, Rosenfeld M et al (2010) Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res 16:2443–2449PubMedCrossRefGoogle Scholar
  143. 143.
    Butowski N, Chang SM, Lamborn KR, Polley MY, Parvataneni R, Hristova-Kazmierski M et al (2010) Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: a phase I study. Neuro Oncol 12:608–613PubMedCrossRefGoogle Scholar
  144. 144.
    Conforti R, Ma Y, Morel Y, Paturel C, Terme M, Viaud S et al (2010) Opposing effects of toll-like receptor (TLR3) signaling in tumors can be therapeutically uncoupled to optimize the anticancer efficacy of TLR3 ligands. Cancer Res 70:490–500PubMedCrossRefGoogle Scholar
  145. 145.
    Chin AI, Miyahira AK, Covarrubias A, Teague J, Guo B, Dempsey PW et al (2010) Toll-like receptor 3-mediated suppression of TRAMP prostate cancer shows the critical role of type I interferons in tumor immune surveillance. Cancer Res 70:2595–2603PubMedCrossRefGoogle Scholar
  146. 146.
    Rehli M (2002) Of mice and men: species variations of Toll-like receptor expression. Trends Immunol 23:375–378PubMedCrossRefGoogle Scholar
  147. 147.
    Lundberg AM, Drexler SK, Monaco C, Williams LM, Sacre SM, Feldmann M et al (2007) Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells: a phenomenon absent from murine cell systems. Blood 110:3245–3252PubMedCrossRefGoogle Scholar
  148. 148.
    Heinz S, Haehnel V, Karaghiosoff M, Schwarzfischer L, Muller M, Krause SW et al (2003) Species-specific regulation of Toll-like receptor 3 genes in men and mice. J Biol Chem 278:21502–21509PubMedCrossRefGoogle Scholar
  149. 149.
    Gowen BB, Wong MH, Jung KH, Sanders AB, Mitchell WM, Alexopoulou L et al (2007) TLR3 is essential for the induction of protective immunity against Punta Toro Virus infection by the double-stranded RNA (dsRNA), poly(I:C12U), but not Poly(I:C): differential recognition of synthetic dsRNA molecules. J Immunol 178:5200–5208PubMedGoogle Scholar
  150. 150.
    Jasani B, Navabi H, Adams M (2009) Ampligen: a potential toll-like 3 receptor adjuvant for immunotherapy of cancer. Vaccine 27:3401–3404PubMedCrossRefGoogle Scholar
  151. 151.
    Hoebe K, Janssen EM, Kim SO, Alexopoulou L, Flavell RA, Han J et al (2003) Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways. Nat Immunol 4:1223–1229PubMedCrossRefGoogle Scholar
  152. 152.
    Datta SK, Redecke V, Prilliman KR, Takabayashi K, Corr M, Tallant T et al (2003) A subset of Toll-like receptor ligands induces cross-presentation by bone marrow-derived dendritic cells. J Immunol 170:4102–4110PubMedGoogle Scholar
  153. 153.
    Longhi MP, Trumpfheller C, Idoyaga J, Caskey M, Matos I, Kluger C et al (2009) Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J Exp Med 206:1589–1602PubMedCrossRefGoogle Scholar
  154. 154.
    Fuertes Marraco SA, Scott CL, Bouillet P, Ives A, Masina S, Vremec D et al (2011) Type I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo. PLoS One 6:e20189PubMedCrossRefGoogle Scholar
  155. 155.
    McCartney S, Vermi W, Gilfillan S, Cella M, Murphy TL, Schreiber RD et al (2009) Distinct and complementary functions of MDA5 and TLR3 in poly(I:C)-mediated activation of mouse NK cells. J Exp Med 206:2967–2976PubMedCrossRefGoogle Scholar
  156. 156.
    Perrot I, Deauvieau F, Massacrier C, Hughes N, Garrone P, Durand I et al (2010) TLR3 and Rig-like receptor on myeloid dendritic cells and Rig-like receptor on human NK cells are both mandatory for production of IFN-gamma in response to double-stranded RNA. J Immunol 185:2080–2088PubMedCrossRefGoogle Scholar
  157. 157.
    Schulz O, Diebold SS, Chen M, Naslund TI, Nolte MA, Alexopoulou L et al (2005) Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature 433:887–892PubMedCrossRefGoogle Scholar
  158. 158.
    Wick DA, Martin SD, Nelson BH, Webb JR (2011) Profound CD8+ T cell immunity elicited by sequential daily immunization with exogenous antigen plus the TLR3 agonist poly(I:C). Vaccine 29:984–993PubMedCrossRefGoogle Scholar
  159. 159.
    Aranda F, Llopiz D, Diaz-Valdes N, Riezu-Boj JI, Bezunartea J, Ruiz M et al (2011) Adjuvant combination and antigen targeting as a strategy to induce polyfunctional and high-avidity T-cell responses against poorly immunogenic tumors. Cancer Res 71:3214–3224PubMedCrossRefGoogle Scholar
  160. 160.
    Salaun B, Greutert M, Romero P (2009) Toll-like receptor 3 is necessary for dsRNA adjuvant effects. Vaccine 27:1841–1847PubMedCrossRefGoogle Scholar
  161. 161.
    Wang Y, Cella M, Gilfillan S, Colonna M (2010) Cutting edge: polyinosinic:polycytidylic acid boosts the generation of memory CD8 T cells through melanoma differentiation-associated protein 5 expressed in stromal cells. J Immunol 184:2751–2755PubMedCrossRefGoogle Scholar
  162. 162.
    Pulko V, Liu X, Krco CJ, Harris KJ, Frigola X, Kwon ED et al (2009) TLR3-stimulated dendritic cells up-regulate B7-H1 expression and influence the magnitude of CD8 T cell responses to tumor vaccination. J Immunol 183:3634–3641PubMedCrossRefGoogle Scholar
  163. 163.
    Lin Q, Fang D, Fang J, Ren X, Yang X, Wen F et al (2011) Impaired wound healing with defective expression of chemokines and recruitment of myeloid cells in TLR3-deficient mice. J Immunol 186:3710–3717PubMedCrossRefGoogle Scholar
  164. 164.
    Paone A, Galli R, Gabellini C, Lukashev D, Starace D, Gorlach A et al (2010) Toll-like receptor 3 regulates angiogenesis and apoptosis in prostate cancer cell lines through hypoxia-inducible factor 1 alpha. Neoplasia 12:539–549PubMedGoogle Scholar
  165. 165.
    Zimmer S, Steinmetz M, Asdonk T, Motz I, Coch C, Hartmann E et al (2011) Activation of endothelial toll-like receptor 3 impairs endothelial function. Circ Res 108:1358–1366PubMedCrossRefGoogle Scholar
  166. 166.
    Berge M, Bonnin P, Sulpice E, Vilar J, Allanic D, Silvestre JS et al (2010) Small interfering RNAs induce target-independent inhibition of tumor growth and vasculature remodeling in a mouse model of hepatocellular carcinoma. Am J Pathol 177:3192–3201PubMedCrossRefGoogle Scholar
  167. 167.
    Chuang TH, Ulevitch RJ (2000) Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8 and hTLR9. Eur Cytokine Netw 11:372–378PubMedGoogle Scholar
  168. 168.
    Robbins SH, Walzer T, Dembele D, Thibault C, Defays A, Bessou G et al (2008) Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling. Genome Biol 9:R17PubMedCrossRefGoogle Scholar
  169. 169.
    Poulin LF, Salio M, Griessinger E, Anjos-Afonso F, Craciun L, Chen JL et al (2010) Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha + dendritic cells. J Exp Med 207:1261–1271PubMedCrossRefGoogle Scholar
  170. 170.
    Jongbloed SL, Kassianos AJ, McDonald KJ, Clark GJ, Ju X, Angel CE et al (2010) Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med 207:1247–1260PubMedCrossRefGoogle Scholar
  171. 171.
    Hart OM, Athie-Morales V, O’Connor GM, Gardiner CM (2005) TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-gamma production. J Immunol 175:1636–1642PubMedGoogle Scholar
  172. 172.
    Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S et al (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303:1526–1529PubMedCrossRefGoogle Scholar
  173. 173.
    Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW et al (2004) Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci USA 101:5598–5603PubMedCrossRefGoogle Scholar
  174. 174.
    Forsbach A, Nemorin JG, Montino C, Muller C, Samulowitz U, Vicari AP et al (2008) Identification of RNA sequence motifs stimulating sequence-specific TLR8-dependent immune responses. J Immunol 180:3729–3738PubMedGoogle Scholar
  175. 175.
    Demaria O, Pagni PP, Traub S, de Gassart A, Branzk N, Murphy AJ et al (2010) TLR8 deficiency leads to autoimmunity in mice. J Clin Invest 120:3651–3662PubMedGoogle Scholar
  176. 176.
    Jurk M, Chikh G, Schulte B, Kritzler A, Richardt-Pargmann D, Lampron C et al (2011) Immunostimulatory potential of silencing RNAs can be mediated by a non-uridine-rich Toll-like receptor 7 motif. Nucleic Acid Ther 21(3):201–214Google Scholar
  177. 177.
    Hornung V, Guenthner-Biller M, Bourquin C, Ablasser A, Schlee M, Uematsu S et al (2005) Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med 11:263–270PubMedCrossRefGoogle Scholar
  178. 178.
    Sledz CA, Holko M, de Veer MJ, Silverman RH, Williams BR (2003) Activation of the interferon system by short-interfering RNAs. Nat Cell Biol 5:834–839PubMedCrossRefGoogle Scholar
  179. 179.
    Kleinman ME, Yamada K, Takeda A, Chandrasekaran V, Nozaki M, Baffi JZ et al (2008) Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452:591–597PubMedCrossRefGoogle Scholar
  180. 180.
    Lan T, Kandimalla ER, Yu D, Bhagat L, Li Y, Wang D et al (2007) Stabilized immune modulatory RNA compounds as agonists of Toll-like receptors 7 and 8. Proc Natl Acad Sci USA 104:13750–13755PubMedCrossRefGoogle Scholar
  181. 181.
    Kandimalla ER, Struthers M, Bett AJ, Wisniewski T, Dubey SA, Jiang W et al (2011) Synthesis and immunological activities of novel Toll-like receptor 7 and 8 agonists. Cell Immunol 270(2):126–134PubMedCrossRefGoogle Scholar
  182. 182.
    Wang D, Precopio M, Lan T, Yu D, Tang JX, Kandimalla ER et al (2010) Antitumor activity and immune response induction of a dual agonist of Toll-like receptors 7 and 8. Mol Cancer Ther 9:1788–1797PubMedCrossRefGoogle Scholar
  183. 183.
    Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M (2004) Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 50:722–733PubMedCrossRefGoogle Scholar
  184. 184.
    Bong AB, Bonnekoh B, Franke I, Schon MP, Ulrich J, Gollnick H (2002) Imiquimod, a topical immune response modifier, in the treatment of cutaneous metastases of malignant melanoma. Dermatology 205:135–138PubMedCrossRefGoogle Scholar
  185. 185.
    Turza K, Dengel LT, Harris RC, Patterson JW, White K, Grosh WW et al (2010) Effectiveness of imiquimod limited to dermal melanoma metastases, with simultaneous resistance of subcutaneous metastasis. J Cutan Pathol 37:94–98PubMedCrossRefGoogle Scholar
  186. 186.
    Wolf IH, Cerroni L, Kodama K, Kerl H (2005) Treatment of lentigo maligna (melanoma in situ) with the immune response modifier imiquimod. Arch Dermatol 141:510–514PubMedCrossRefGoogle Scholar
  187. 187.
    Wolf IH, Smolle J, Binder B, Cerroni L, Richtig E, Kerl H (2003) Topical imiquimod in the treatment of metastatic melanoma to skin. Arch Dermatol 139:273–276PubMedCrossRefGoogle Scholar
  188. 188.
    Hirsch I, Caux C, Hasan U, Bendriss-Vermare N, Olive D (2010) Impaired Toll-like receptor 7 and 9 signaling: from chronic viral infections to cancer. Trends Immunol 31:391–397PubMedCrossRefGoogle Scholar
  189. 189.
    Dudek AZ, Yunis C, Harrison LI, Kumar S, Hawkinson R, Cooley S et al (2007) First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer. Clin Cancer Res 13:7119–7125PubMedCrossRefGoogle Scholar
  190. 190.
    Dummer R, Hauschild A, Becker JC, Grob JJ, Schadendorf D, Tebbs V et al (2008) An exploratory study of systemic administration of the toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma. Clin Cancer Res 14:856–864PubMedCrossRefGoogle Scholar
  191. 191.
    Inglefield JR, Dumitru CD, Alkan SS, Gibson SJ, Lipson KE, Tomai MA et al (2008) TLR7 agonist 852A inhibition of tumor cell proliferation is dependent on plasmacytoid dendritic cells and type I IFN. J Interferon Cytokine Res 28:253–263PubMedCrossRefGoogle Scholar
  192. 192.
    Cohen P, Northfelt D, Weiss GJ, Von Hoff DD, Manjarrez K, Ditesch G et al (2011) Phase I clinical trial of VTX-2337, a selective toll-like receptor 8 (TLR8) agonist, in patients with advanced solid tumors. J Clin Oncol 29:2537CrossRefGoogle Scholar
  193. 193.
    Bourquin C, Hotz C, Noerenberg D, Voelkl A, Heidegger S, Roetzer LC et al (2011) Systemic cancer therapy with a small molecule agonist of Toll-like receptor 7 can be improved by circumventing TLR tolerance. Cancer Res 71:5123–5133PubMedCrossRefGoogle Scholar
  194. 194.
    Lu H, Wagner WM, Gad E, Yang Y, Duan H, Amon LM et al (2010) Treatment failure of a TLR-7 agonist occurs due to self-regulation of acute inflammation and can be overcome by IL-10 blockade. J Immunol 184:5360–5367PubMedCrossRefGoogle Scholar
  195. 195.
    Palamara F, Meindl S, Holcmann M, Luhrs P, Stingl G, Sibilia M (2004) Identification and characterization of pDC-like cells in normal mouse skin and melanomas treated with imiquimod. J Immunol 173:3051–3061PubMedGoogle Scholar
  196. 196.
    Stary G, Bangert C, Tauber M, Strohal R, Kopp T, Stingl G (2007) Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells. J Exp Med 204:1441–1451PubMedCrossRefGoogle Scholar
  197. 197.
    Gorden KB, Gorski KS, Gibson SJ, Kedl RM, Kieper WC, Qiu X et al (2005) Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol 174:1259–1268PubMedGoogle Scholar
  198. 198.
    Gorski KS, Waller EL, Bjornton-Severson J, Hanten JA, Riter CL, Kieper WC et al (2006) Distinct indirect pathways govern human NK-cell activation by TLR-7 and TLR-8 agonists. Int Immunol 18:1115–1126PubMedCrossRefGoogle Scholar
  199. 199.
    Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T et al (2005) Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309:1380–1384PubMedCrossRefGoogle Scholar
  200. 200.
    Cherfils-Vicini J, Platonova S, Gillard M, Laurans L, Validire P, Caliandro R et al (2010) Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. J Clin Invest 120:1285–1297PubMedCrossRefGoogle Scholar
  201. 201.
    Spranger S, Javorovic M, Burdek M, Wilde S, Mosetter B, Tippmer S et al (2010) Generation of Th1-polarizing dendritic cells using the TLR7/8 agonist CL075. J Immunol 185:738–747PubMedCrossRefGoogle Scholar
  202. 202.
    Pufnock JS, Cigal M, Rolczynski LS, Andersen-Nissen E, Wolfl M, McElrath MJ et al (2011) Priming CD8+ T cells with dendritic cells matured using TLR4 and TLR7/8 ligands together enhances generation of CD8+ T cells retaining CD28. Blood 117:6542–6551PubMedCrossRefGoogle Scholar
  203. 203.
    Zobywalski A, Javorovic M, Frankenberger B, Pohla H, Kremmer E, Bigalke I et al (2007) Generation of clinical grade dendritic cells with capacity to produce biologically active IL-12p70. J Transl Med 5:18PubMedCrossRefGoogle Scholar
  204. 204.
    Shackleton M, Davis ID, Hopkins W, Jackson H, Dimopoulos N, Tai T et al (2004) The impact of imiquimod, a Toll-like receptor-7 ligand (TLR7L), on the immunogenicity of melanoma peptide vaccination with adjuvant Flt3 ligand. Cancer Immun 4:9PubMedGoogle Scholar
  205. 205.
    Prins RM, Craft N, Bruhn KW, Khan-Farooqi H, Koya RC, Stripecke R et al (2006) The TLR-7 agonist, imiquimod, enhances dendritic cell survival and promotes tumor antigen-specific T cell priming: relation to central nervous system antitumor immunity. J Immunol 176:157–164PubMedGoogle Scholar
  206. 206.
    Ma F, Zhang J, Zhang J, Zhang C (2010) The TLR7 agonists imiquimod and gardiquimod improve DC-based immunotherapy for melanoma in mice. Cell Mol Immunol 7:381–388PubMedCrossRefGoogle Scholar
  207. 207.
    Mahnke K, Qian Y, Fondel S, Brueck J, Becker C, Enk AH (2005) Targeting of antigens to activated dendritic cells in vivo cures metastatic melanoma in mice. Cancer Res 65:7007–7012PubMedCrossRefGoogle Scholar
  208. 208.
    Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig MC, Steinman RM (2002) Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J Exp Med 196:1627–1638PubMedCrossRefGoogle Scholar
  209. 209.
    Adams S, O’Neill DW, Nonaka D, Hardin E, Chiriboga L, Siu K et al (2008) Immunization of malignant melanoma patients with full-length NY-ESO-1 protein using TLR7 agonist imiquimod as vaccine adjuvant. J Immunol 181:776–784PubMedGoogle Scholar
  210. 210.
    Edwards AD, Diebold SS, Slack EM, Tomizawa H, Hemmi H, Kaisho T et al (2003) Toll-like receptor expression in murine DC subsets: lack of TLR7 expression by CD8 alpha+ DC correlates with unresponsiveness to imidazoquinolines. Eur J Immunol 33:827–833PubMedCrossRefGoogle Scholar
  211. 211.
    Pedersen G, Andresen L, Matthiessen MW, Rask-Madsen J, Brynskov J (2005) Expression of Toll-like receptor 9 and response to bacterial CpG oligodeoxynucleotides in human intestinal epithelium. Clin Exp Immunol 141:298–306PubMedCrossRefGoogle Scholar
  212. 212.
    Platz J, Beisswenger C, Dalpke A, Koczulla R, Pinkenburg O, Vogelmeier C et al (2004) Microbial DNA induces a host defense reaction of human respiratory epithelial cells. J Immunol 173:1219–1223PubMedGoogle Scholar
  213. 213.
    Lebre MC, van der Aar AM, van Baarsen L, van Capel TM, Schuitemaker JH, Kapsenberg ML et al (2007) Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9. J Invest Dermatol 127:331–341PubMedCrossRefGoogle Scholar
  214. 214.
    Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H et al (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745PubMedCrossRefGoogle Scholar
  215. 215.
    Copin R, De BP, Carlier Y, Letesson JJ, Muraille E (2007) MyD88-dependent activation of B220-CD11b+LY-6C+ dendritic cells during Brucella melitensis infection. J Immunol 178:5182–5191PubMedGoogle Scholar
  216. 216.
    Lee KS, Scanga CA, Bachelder EM, Chen Q, Snapper CM (2007) TLR2 synergizes with both TLR4 and TLR9 for induction of the MyD88-dependent splenic cytokine and chemokine response to Streptococcus pneumoniae. Cell Immunol 245:103–110PubMedCrossRefGoogle Scholar
  217. 217.
    Bafica A, Scanga CA, Feng CG, Leifer C, Cheever A, Sher A (2005) TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis. J Exp Med 202:1715–1724PubMedCrossRefGoogle Scholar
  218. 218.
    Anderson AE, Worku ML, Khamri W, Bamford KB, Walker MM, Thursz MR (2007) TLR9 polymorphisms determine murine lymphocyte responses to Helicobacter: results from a genome-wide scan. Eur J Immunol 37:1548–1561PubMedCrossRefGoogle Scholar
  219. 219.
    Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A (2003) Toll-like receptor 9-mediated recognition of herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med 198:513–520PubMedCrossRefGoogle Scholar
  220. 220.
    Sasai M, Linehan MM, Iwasaki A (2010) Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3. Science 329:1530–1534PubMedCrossRefGoogle Scholar
  221. 221.
    Krug A, French AR, Barchet W, Fischer JA, Dzionek A, Pingel JT et al (2004) TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 21:107–119PubMedCrossRefGoogle Scholar
  222. 222.
    Zhu J, Huang X, Yang Y (2007) Innate immune response to adenoviral vectors is mediated by both Toll-like receptor-dependent and -independent pathways. J Virol 81:3170–3180PubMedCrossRefGoogle Scholar
  223. 223.
    Fathallah I, Parroche P, Gruffat H, Zannetti C, Johansson H, Yue J et al (2010) EBV latent membrane protein 1 is a negative regulator of TLR9. J Immunol 185:6439–6447PubMedCrossRefGoogle Scholar
  224. 224.
    Andersen JM, Al-Khairy D, Ingalls RR (2006) Innate immunity at the mucosal surface: role of toll-like receptor 3 and toll-like receptor 9 in cervical epithelial cell responses to microbial pathogens. Biol Reprod 74:824–831PubMedCrossRefGoogle Scholar
  225. 225.
    Kandimalla ER, Bhagat L, Li Y, Yu D, Wang D, Cong YP et al (2005) Immunomodulatory oligonucleotides containing a cytosine-phosphate-2′-deoxy-7-deazaguanosine motif as potent toll-like receptor 9 agonists. Proc Natl Acad Sci USA 102:6925–6930PubMedCrossRefGoogle Scholar
  226. 226.
    Wakefield D, Gray P, Chang J, Di GN, McCluskey P (2010) The role of PAMPs and DAMPs in the pathogenesis of acute and recurrent anterior uveitis. Br J Ophthalmol 94:271–274PubMedCrossRefGoogle Scholar
  227. 227.
    Rubartelli A, Lotze MT (2007) Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol 28:429–436PubMedCrossRefGoogle Scholar
  228. 228.
    Garg AD, Nowis D, Golab J, Vandenabeele P, Krysko DV, Agostinis P (2010) Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation. Biochim Biophys Acta 1805:53–71PubMedGoogle Scholar
  229. 229.
    Carta S, Castellani P, Delfino L, Tassi S, Vene R, Rubartelli A (2009) DAMPs and inflammatory processes: the role of redox in the different outcomes. J Leukoc Biol 86:549–555PubMedCrossRefGoogle Scholar
  230. 230.
    Gilliet M, Lande R (2008) Antimicrobial peptides and self-DNA in autoimmune skin inflammation. Curr Opin Immunol 20:401–407PubMedCrossRefGoogle Scholar
  231. 231.
    Vollmer J, Weeratna R, Payette P, Jurk M, Schetter C, Laucht M et al (2004) Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities. Eur J Immunol 34:251–262PubMedCrossRefGoogle Scholar
  232. 232.
    Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R et al (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–549PubMedCrossRefGoogle Scholar
  233. 233.
    Brinkmann MM, Spooner E, Hoebe K, Beutler B, Ploegh HL, Kim YM (2007) The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling. J Cell Biol 177:265–275PubMedCrossRefGoogle Scholar
  234. 234.
    Tabeta K, Hoebe K, Janssen EM, Du X, Georgel P, Crozat K et al (2006) The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat Immunol 7:156–164PubMedCrossRefGoogle Scholar
  235. 235.
    Kim YM, Brinkmann MM, Paquet ME, Ploegh HL (2008) UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature 452:234–238PubMedCrossRefGoogle Scholar
  236. 236.
    Sepulveda FE, Maschalidi S, Colisson R, Heslop L, Ghirelli C, Sakka E et al (2009) Critical role for asparagine endopeptidase in endocytic Toll-like receptor signaling in dendritic cells. Immunity 31:737–748PubMedCrossRefGoogle Scholar
  237. 237.
    Ewald SE, Lee BL, Lau L, Wickliffe KE, Shi GP, Chapman HA et al (2008) The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature 456:658–662PubMedCrossRefGoogle Scholar
  238. 238.
    Park B, Brinkmann MM, Spooner E, Lee CC, Kim YM, Ploegh HL (2008) Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nat Immunol 9:1407–1414PubMedCrossRefGoogle Scholar
  239. 239.
    Ewald SE, Engel A, Lee J, Wang M, Bogyo M, Barton GM (2011) Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase. J Exp Med 208:643–651PubMedCrossRefGoogle Scholar
  240. 240.
    Kemp TJ, Elzey BD, Griffith TS (2003) Plasmacytoid dendritic cell-derived IFN-alpha induces TNF-related apoptosis-inducing ligand/Apo-2L-mediated antitumor activity by human monocytes following CpG oligodeoxynucleotide stimulation. J Immunol 171:212–218PubMedGoogle Scholar
  241. 241.
    Bekeredjian-Ding I, Jego G (2009) Toll-like receptors—sentries in the B-cell response. Immunology 128:311–323PubMedCrossRefGoogle Scholar
  242. 242.
    Hanten JA, Vasilakos JP, Riter CL, Neys L, Lipson KE, Alkan SS et al (2008) Comparison of human B cell activation by TLR7 and TLR9 agonists. BMC Immunol 9:39PubMedCrossRefGoogle Scholar
  243. 243.
    Bernasconi NL, Traggiai E, Lanzavecchia A (2002) Maintenance of serological memory by polyclonal activation of human memory B cells. Science 298:2199–2202PubMedCrossRefGoogle Scholar
  244. 244.
    Eckl-Dorna J, Batista FD (2009) BCR-mediated uptake of antigen linked to TLR9 ligand stimulates B-cell proliferation and antigen-specific plasma cell formation. Blood 113:3969–3977PubMedCrossRefGoogle Scholar
  245. 245.
    Holtick U, Scheulen ME, von Bergwelt-Baildon MS, Weihrauch MR (2011) Toll-like receptor 9 agonists as cancer therapeutics. Expert Opin Investig Drugs 20:361–372PubMedCrossRefGoogle Scholar
  246. 246.
    Goodchild A, Nopper N, Craddock A, Law T, King A, Fanning G et al (2009) Primary leukocyte screens for innate immune agonists. J Biomol Screen 14:723–730PubMedCrossRefGoogle Scholar
  247. 247.
    Agrawal S, Kandimalla ER (2007) Synthetic agonists of Toll-like receptors 7, 8 and 9. Biochem Soc Trans 35:1461–1467PubMedCrossRefGoogle Scholar
  248. 248.
    Krieg AM (2008) Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene 27:161–167PubMedCrossRefGoogle Scholar
  249. 249.
    Rakoff-Nahoum S, Medzhitov R (2009) Toll-like receptors and cancer. Nat Rev Cancer 9:57–63PubMedCrossRefGoogle Scholar
  250. 250.
    van Ojik HH, Bevaart L, Dahle CE, Bakker A, Jansen MJ, van Vugt MJ et al (2003) CpG-A and B oligodeoxynucleotides enhance the efficacy of antibody therapy by activating different effector cell populations. Cancer Res 63:5595–5600PubMedGoogle Scholar
  251. 251.
    Schmidt C (2007) Clinical setbacks for toll-like receptor 9 agonists in cancer. Nat Biotechnol 25:825–826PubMedCrossRefGoogle Scholar
  252. 252.
    Brody JD, Ai WZ, Czerwinski DK, Torchia JA, Levy M, Advani RH et al (2010) In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J Clin Oncol 28:4324–4332PubMedCrossRefGoogle Scholar
  253. 253.
    Kochling J, Prada J, Bahrami M, Stripecke R, Seeger K, Henze G et al (2008) Anti-tumor effect of DNA-based vaccination and dSLIM immunomodulatory molecules in mice with Ph+ acute lymphoblastic leukaemia. Vaccine 26:4669–4675PubMedCrossRefGoogle Scholar
  254. 254.
    Vaisanen MR, Vaisanen T, Jukkola-Vuorinen A, Vuopala KS, Desmond R, Selander KS et al (2010) Expression of toll-like receptor-9 is increased in poorly differentiated prostate tumors. Prostate 70:817–824PubMedCrossRefGoogle Scholar
  255. 255.
    Gonzalez-Reyes S, Marin L, Gonzalez L, Gonzalez LO, del Casar JM, Lamelas ML et al (2010) Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis. BMC Cancer 10:665PubMedCrossRefGoogle Scholar
  256. 256.
    Kuninaka N, Kurata M, Yamamoto K, Suzuki S, Umeda S, Kirimura S et al (2010) Expression of Toll-like receptor 9 in bone marrow cells of myelodysplastic syndromes is down-regulated during transformation to overt leukemia. Exp Mol Pathol 88:293–298PubMedCrossRefGoogle Scholar
  257. 257.
    Daud II, Scott ME, Ma Y, Shiboski S, Farhat S, Moscicki AB (2011) Association between toll-like receptor expression and human papillomavirus type 16 persistence. Int J Cancer 128:879–886PubMedCrossRefGoogle Scholar
  258. 258.
    Chiron D, Bekeredjian-Ding I, Pellat-Deceunynck C, Bataille R, Jego G (2008) Toll-like receptors: lessons to learn from normal and malignant human B cells. Blood 112:2205–2213PubMedCrossRefGoogle Scholar
  259. 259.
    Yu L, Chen S (2008) Toll-like receptors expressed in tumor cells: targets for therapy. Cancer Immunol Immunother 57:1271–1278PubMedCrossRefGoogle Scholar
  260. 260.
    Gekeler V, Gimmnich P, Hofmann HP, Grebe C, Rommele M, Leja A et al (2006) G3139 and other CpG-containing immunostimulatory phosphorothioate oligodeoxynucleotides are potent suppressors of the growth of human tumor xenografts in nude mice. Oligonucleotides 16:83–93PubMedCrossRefGoogle Scholar
  261. 261.
    Wang H, Rayburn ER, Wang W, Kandimalla ER, Agrawal S, Zhang R (2006) Chemotherapy and chemosensitization of non-small cell lung cancer with a novel immunomodulatory oligonucleotide targeting Toll-like receptor 9. Mol Cancer Ther 5:1585–1592PubMedCrossRefGoogle Scholar
  262. 262.
    Ilvesaro JM, Merrell MA, Swain TM, Davidson J, Zayzafoon M, Harris KW et al (2007) Toll like receptor-9 agonists stimulate prostate cancer invasion in vitro. Prostate 67:774–781PubMedCrossRefGoogle Scholar
  263. 263.
    El AA, Sonabend AM, Han Y, Lesniak MS (2006) Stimulation of TLR9 with CpG ODN enhances apoptosis of glioma and prolongs the survival of mice with experimental brain tumors. Glia 54:526–535CrossRefGoogle Scholar
  264. 264.
    Fischer SF, Rehm M, Bauer A, Hofling F, Kirschnek S, Rutz M et al (2005) Toll-like receptor 9 signaling can sensitize fibroblasts for apoptosis. Immunol Lett 97:115–122PubMedCrossRefGoogle Scholar
  265. 265.
    Jozsef L, Khreiss T, Filep JG (2004) CpG motifs in bacterial DNA delay apoptosis of neutrophil granulocytes. FASEB J 18:1776–1778PubMedGoogle Scholar
  266. 266.
    Chang YJ, Wu MS, Lin JT, Chen CC (2005) Helicobacter pylori-induced invasion and angiogenesis of gastric cells is mediated by cyclooxygenase-2 induction through TLR2/TLR9 and promoter regulation. J Immunol 175:8242–8252PubMedGoogle Scholar
  267. 267.
    Damiano V, Caputo R, Bianco R, D’Armiento FP, Leonardi A, De PS et al (2006) Novel toll-like receptor 9 agonist induces epidermal growth factor receptor (EGFR) inhibition and synergistic antitumor activity with EGFR inhibitors. Clin Cancer Res 12:577–583PubMedCrossRefGoogle Scholar
  268. 268.
    Nierkens S, den Brok MH, Garcia Z, Togher S, Wagenaars J, Wassink M et al (2011) Immune adjuvant efficacy of CpG oligonucleotide in cancer treatment is founded specifically upon TLR9 function in plasmacytoid dendritic cells. Cancer Res 71(20):6428–6437PubMedCrossRefGoogle Scholar
  269. 269.
    Labidi-Galy SI, Sisirak V, Meeus P, Gobert M, Treilleux I, Bajard A et al (2011) Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer. Cancer Res 71:5423PubMedCrossRefGoogle Scholar
  270. 270.
    Hartmann E, Wollenberg B, Rothenfusser S, Wagner M, Wellisch D, Mack B et al (2003) Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res 63:6478–6487PubMedGoogle Scholar
  271. 271.
    Perrot I, Blanchard D, Freymond N, Isaac S, Guibert B, Pacheco Y et al (2007) Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage. J Immunol 178:2763–2769PubMedGoogle Scholar
  272. 272.
    Dolganiuc A, Chang S, Kodys K, Mandrekar P, Bakis G, Cormier M et al (2006) Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol 177:6758–6768PubMedGoogle Scholar
  273. 273.
    Conry SJ, Milkovich KA, Yonkers NL, Rodriguez B, Bernstein HB, Asaad R et al (2009) Impaired plasmacytoid dendritic cell (PDC)-NK cell activity in viremic human immunodeficiency virus infection attributable to impairments in both PDC and NK cell function. J Virol 83:11175–11187PubMedCrossRefGoogle Scholar
  274. 274.
    Ulsenheimer A, Gerlach JT, Jung MC, Gruener N, Wachtler M, Backmund M et al (2005) Plasmacytoid dendritic cells in acute and chronic hepatitis C virus infection. Hepatology 41:643–651PubMedCrossRefGoogle Scholar
  275. 275.
    Kang DC, Gopalkrishnan RV, Lin L, Randolph A, Valerie K, Pestka S et al (2004) Expression analysis and genomic characterization of human melanoma differentiation associated gene-5, mda-5: a novel type I interferon-responsive apoptosis-inducing gene. Oncogene 23:1789–1800PubMedCrossRefGoogle Scholar
  276. 276.
    Kovacsovics M, Martinon F, Micheau O, Bodmer JL, Hofmann K, Tschopp J (2002) Overexpression of Helicard, a CARD-containing helicase cleaved during apoptosis, accelerates DNA degradation. Curr Biol 12:838–843PubMedCrossRefGoogle Scholar
  277. 277.
    Tormo D, Checinska A, Alonso-Curbelo D, Perez-Guijarro E, Canon E, Riveiro-Falkenbach E et al (2009) Targeted activation of innate immunity for therapeutic induction of autophagy and apoptosis in melanoma cells. Cancer Cell 16:103–114PubMedCrossRefGoogle Scholar
  278. 278.
    Poeck H, Besch R, Maihoefer C, Renn M, Tormo D, Morskaya SS et al (2008) 5′-Triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma. Nat Med 14:1256–1263PubMedCrossRefGoogle Scholar
  279. 279.
    Besch R, Poeck H, Hohenauer T, Senft D, Hacker G, Berking C et al (2009) Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells. J Clin Invest 119:2399–2411PubMedGoogle Scholar
  280. 280.
    Kubler K, Pesch CT, Gehrke N, Riemann S, Dassler J, Coch C et al (2011) Immunogenic cell death of human ovarian cancer cells induced by cytosolic poly(I:C) leads to myeloid cell maturation and activates NK cells. Eur J Immunol 41(10):3028–3039PubMedCrossRefGoogle Scholar
  281. 281.
    Liu TX, Zhang JW, Tao J, Zhang RB, Zhang QH, Zhao CJ et al (2000) Gene expression networks underlying retinoic acid-induced differentiation of acute promyelocytic leukemia cells. Blood 96:1496–1504PubMedGoogle Scholar
  282. 282.
    Jiang LJ, Zhang NN, Ding F, Li XY, Chen L, Zhang HX et al (2011) RA-inducible gene-I induction augments STAT1 activation to inhibit leukemia cell proliferation. Proc Natl Acad Sci USA 108:1897–1902PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Nadège Goutagny
    • 1
  • Yann Estornes
    • 1
  • Uzma Hasan
    • 2
  • Serge Lebecque
    • 1
  • Christophe Caux
    • 1
  1. 1.Université de Lyon, Université Lyon IUMR INSERM 1052 CNRS 5286, Centre de Recherche en Cancérologie de Lyon, Centre Léon BérardLyonFrance
  2. 2.Université de Lyon, FranceLyonFrance

Personalised recommendations