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Cellular and Molecular Biology Letters

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Volume 14, Issue 2 (Jun 2009)

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

Anna Wolska
  • Department of Hematology, Medical University of Łódź, Ciołkowskiego 2, 93-513, Łódź, Poland
  • Email:
/ Ewa Lech-Marańda
  • Department of Hematology, Medical University of Łódź, Ciołkowskiego 2, 93-513, Łódź, Poland
  • Email:
/ Tadeusz Robak
  • Department of Hematology, Medical University of Łódź, Ciołkowskiego 2, 93-513, Łódź, Poland
  • Email:
Published Online: 2009-03-13 | DOI: https://doi.org/10.2478/s11658-008-0048-z

Abstract

Toll-like receptors (TLRs) have been described as major components of the innate immune system, recognizing the conserved molecular structures found in the large groups of pathogens called pathogen-associated molecular patterns (PAMPs). TLR expression is ubiquitous, from epithelial to immunocompetent cells. TLR ligation triggers several adapter proteins and downstream kinases, leading to the induction of key pro-inflammatory mediators but also anti-inflammatory and anti-tumor cytokines. The result of this activation goes beyond innate immunity to shape the adaptive responses against pathogens and tumor cells, and maintains host homeostasis via cell debris utilization. TLRs have already become potent targets in infectious disease treatment and vaccine therapy and in neoplastic disease treatment, due to their ability to enhance antigen presentation. However, some studies show the dual effect of TLR stimulation on malignant cells: they can be proapoptotic or promote survival under different conditions. It is therefore crucial to design further studies assessing the biology of these receptors in normal and transformed cells. The established role of TLRs in human disease therapy is based on TLR7 and TLR4 agonists, respectively for the novel treatment of some types of skin cancer and for the anti-hepatitis B virus vaccine. Some clinical trials involving TLR agonists as potent enhancers of the anti-tumor response in solid tumors have begun.

Keywords: Toll-like receptors; Innate immunity; Treatment; Carcinogenesis; Tumor; Vaccine; Dendritic cells

  • [1] Myeong, S.L. and Young-Joon, K. Pattern-recognition receptor signaling initiated from extracellular, membrane, and cytoplasmic space. Mol. Cells 23 (2007) 1–10. Google Scholar

  • [2] Anderson, K.V., Jurgens, G. and Nusslein-Volhard, C. Establishment of dorsal-ventral polarity in the Drosophila embryo: genetic studies on the role of the Toll gene product. Cell 42 (1995) 779–789. Google Scholar

  • [3] Rosetto, M., Engström, Y., Baldari, C.T., Telford, J.L. and Hultmark, D. Signals from the IL-1 receptor homolog, Toll, can activate an immune response in a Drosophila hemocyte cell line. Biochem. Biophys. Res. Commun. 209 (1995) 111–116. Google Scholar

  • [4] Gay, N.J. and Keith, F.J. Drosophila Toll and IL-1 receptor. Nature 351 (1991) 355–356. Google Scholar

  • [5] Medzhitov, R., Preston-Hurlburt, P. and Janeway, C.A.Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388 (1997) 394. Google Scholar

  • [6] Hopkins, P.A. and Sriskandan, S. Mammalian Toll-like receptors: to immunity and beyond. Clin. Exp. Immunol. 140 (2005) 395–407. Google Scholar

  • [7] Bell, J.K., Mullen, G.E., Leifer, C.A., Mazzoni, A., Davies, D.R. and Segal, D.M. Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol. 24 (2003) 528–533. CrossrefGoogle Scholar

  • [8] Ozinsky, A., Underhill, D.M., Fontenot, J.D., Hajjar, A.M., Smith, K.D., Wilson, C.B., Schroeder, L. and Aderem, A. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc. Natl. Acad. Sci. USA 97 (2000) 13766–13771. CrossrefGoogle Scholar

  • [9] Meng, G., Grabiec, A., Vallon, M., Ebe, B., Hampel, S., Bessler, W., Wagner, H. and Kirschning, C.J. Cellular recognition of tri-/di-palmitoylated peptides is independent from a domain encompassing the N-terminal seven leucine-rich repeat (LRR)/LRR-like motifs of TLR2. J. Biol. Chem. 278 (2003) 39822–39829. Google Scholar

  • [10] Roach, J.C., Glusman, G., Rowen, L., Kaur, A., Purcell, M.K., Smith, K.D., Hood, L.E. and Aderem, A. The evolution of vertebrate Toll-like receptors. Proc. Natl. Acad. Sci. USA 102 (2005) 9577–9582. CrossrefGoogle Scholar

  • [11] Takeuchi, O., Kawai, T., Mühlradt, P.F., Morr, M., Radolf, J.D., Zychlinsky, A., Takeda, K. and Akira, S. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol. 13 (2001) 933–940. CrossrefGoogle Scholar

  • [12] Takeuchi, O., Sato, S., Horiuchi, T., Hoshino, K., Takeda, K., Dong, Z., Modlin, R.L. and Akira, S. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol. 169 (2002) 10–14. Google Scholar

  • [13] Iwaki, D., Mitsuazawa, H. and Murakami, S. The extracellular toll-like receptor 2 domain directly binds peptidoglycan derived from Staphylococcus aureus. J. Biol. Chem. 277 (2002) 24315–24320. Google Scholar

  • [14] Means, T.K., Lien, E., Yoshimura, A., Wang, S., Golenbock, D.T. and Fenton, M.J. The CD14 ligands lipoarabinomannan and lipopolysaccharide differ in their requirement for Toll-like receptors. J. Immunol. 163 (1999) 6748–6755. Google Scholar

  • [15] Gantner, B.N., Simmons, R.M., Canavera, S.J., Akira, S. and Underhill, D.M. Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J. Exp. Med. 197 (2003) 1107–1117. Google Scholar

  • [16] Alexopoulou, L., Holt, A.C., Medzhitov, R. and Flavell, R.A. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413 (2001) 732–738. Google Scholar

  • [17] Matsukura, S., Kokubu, F., Kurokawa, M., Kawaguchi, M., Ieki, K., Kuga, H., Odaka, M., Suzuki, S., Watanabe, S., Takeuchi, H., Kasama, T. and Adachi, M. Synthetic double-stranded RNA induces multiple genes related to inflammation through Toll-like receptor 3 depending on NF-kappaB and/or IRF-3 in airway epithelial cells. Clin. Exp. Allergy 36 (2006) 1049–1062. CrossrefGoogle Scholar

  • [18] Yang, H., Young, D.W., Gusovsky, F. and Chow, J.C. Cellular events mediated by lipopolysaccharide-stimulated toll-like receptor 4. MD-2 is required for activation of mitogen-activated protein kinases and Elk-1. J. Biol. Chem. 275 (2002) 20861–20866. Google Scholar

  • [19] Rallabhandi, P., Bell, J., Boukhvalova, M.S., Medvedev, A., Lorenz, E., Arditi, M., Hemming, V.G., Blanco, J.C., Segal, D.M. and Vogel, S.N. Analysis of TLR4 polymorphic variants: new insights into TLR4/MD-2/CD14 stoichiometry, structure, and signaling. J. Immunol. 177 (2006) 322–332. Google Scholar

  • [20] Hayashi, F., Smith, K.D., Ozinsky, A., Hawn, T.R., Yi, E.C., Goodlett, D.R., Eng, J.K., Akira, S., Underhill, D.M. and Aderem, A. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410 (2001) 1099–1103. Google Scholar

  • [21] Smith, K.D., Andersen-Nissen, E., Hayashi, F., Strobe, K., Bergman, M.A., Barrett, S.L., Cookson, B.T. and Aderem, A. Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat. Immunol. 4 (2003) 1247–1253. Google Scholar

  • [22] Heil, F., Hemmi, H., Hochrein, H., Ampenberger, F., Kirschning, C., Akira, S., Lipford, G., Wagner, H. and Bauer, S. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303 (2004) 1526–1529. Google Scholar

  • [23] Jurk, M., Heil, F., Vollmer, J., Schetter, C., Krieg, A.M., Wagner, H., Lipford, G. and Bauer, S. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat. Immunol. 3 (2002) 499. Google Scholar

  • [24] Heil, F., Ahmad-Nejad, P., Hemmi, H., Hochrein, H., Ampenberger, F., Gellert, T., Dietrich, H., Lipford, G., Takeda, K., Akira, S., Wagner, H. and Bauer, S. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur. J. Immunol. 33 (2003) 2987–2997. CrossrefGoogle Scholar

  • [25] Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K. and Akira, S. A Tolllike receptor recognizes bacterial DNA. Nature 408 (2000) 740–745. Google Scholar

  • [26] Jurk, M. and Vollmer, J. Therapeutic applications of synthetic CpG oligodeoxynucleotides as TLR9 agonists for immune modulation. BioDrugs. 21 (2007) 387–401. CrossrefGoogle Scholar

  • [27] Li, M., Carpio, D.F., Zheng, Y., Bruzzo, P., Singh, V., Ouaaz, F., Medzhitov, R.M. and Beg, A.A. An essential role of the NF-kappa B/Toll-like receptor pathway in induction of inflammatory and tissue-repair gene expression by necrotic cells. J. Immunol. 166 (2001) 7128–7135. Google Scholar

  • [28] Basu, S., Binder, R.J., Suto, R., Anderson, K.M. and Srivastava, P.K. Necrotic but not apoptotic cell death releases heat Shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int. Immunol. 12 (2000) 1539–1546. CrossrefGoogle Scholar

  • [29] Wang, Y., Kelly, C.G., Singh, M., McGowan, E.G., Carrara, A.S., Bergmeier, L.A. and Lehner, T. Stimulation of Th1-polarizing cytokines, CC chemokines, maturation of dendritic cells, and adjuvant function by the peptide binding fragment of heat Shock protein 70. J. Immunol. 169 (2002) 2422–2429. Google Scholar

  • [30] Abulafia-Lapid, R., Elias, D., Raz, I., Keren-Zur, Y., Atlan, H. and Cohen, I.R. T-cell proliferative responses of type 1 diabetes patients and healthy individuals to human hsp60 and its peptides. J. Autoimmun. 12 (1999) 121–129. CrossrefGoogle Scholar

  • [31] Szewczuk, M.R. and Depew, W.T. Evidence for T lymphocyte reactivity to the 65 kilodalton heat Shock protein of mycobacterium in active Crohn’s disease. Clin. Invest. Med. 15 (1992) 494–505. Google Scholar

  • [32] Bausinger, H., Lipsker, D., Ziylan, U., Manié, S., Briand, J.P., Cazenave, J.P., Muller, S., Haeuw, J.F., Ravanat, C., de la Salle, H. and Hanau, D. Endotoxin-free heat-Shock protein 70 fails to induce APC activation. Eur. J. Immunol. 32 (2002) 3708–3713. CrossrefGoogle Scholar

  • [33] Gao, B. and Tsan, M.F. Recombinant human heat Shock protein 60 does not induce the release of tumor necrosis factor alpha from murine macrophages. J. Biol. Chem. 278 (2003) 22523–22529. CrossrefGoogle Scholar

  • [34] Kariko, K., Ni, H., Capodici, J., Lamphier, M. and Weissman, D. mRNA is an endogenous ligand for toll-like receptor 3. J. Biol. Chem. 279 (2004) 12542–12550. Google Scholar

  • [35] Kowalski, M.L., Wolska, A., Grzegorczyk, J., Hilt, J., Jarzebska, M., Drobniewski, M., Synder, M. and Kurowski, M. Increased responsiveness to toll-like receptor 4 stimulation in peripheral blood mononuclear cells from patients with recent onset rheumatoid arthritis. Mediators Inflamm. (2008) 132732. Google Scholar

  • [36] Kawai, T. and Akira, S. TLR signaling. Cell Death Differ. 13 (2006) 816–825. Google Scholar

  • [37] Bjorkbacka, H., Fitzgerald, K.A., Huet, F., Li X., Gregory, J.A., Lee, M.A., Ordija, C.M., Dowley, N.E., Golenbock, D.T. and Freeman, M.W. The induction of macrophage gene expression by LPS predominantly utilizes Myd88-independent signaling cascades. Physiol. Genomics 19 (2004) 319–330. CrossrefGoogle Scholar

  • [38] Zhao, J. and Wu, X.Y. Triggering of toll-like receptors 2 and 4 by Aspergillus fumigatus conidia in immortalized human corneal epithelial cells to induce inflammatory cytokines. Chin. Med. J. (Engl). 121 (2008) 450–454. Google Scholar

  • [39] Covert, M.W., Leung, T.H., Gaston, J.E. and Baltimore, D. Achieving stability of lipopolysaccharide-induced NF-kappaB activation. Science 309 (2005) 1854–1857. Google Scholar

  • [40] Wang, J.E., Jorgensen, P.F., Almlof, M., Thiemermann, C., Foster, S.J., Aasen, A.O. and Solberg, R. Peptidoglycan and lipoteichoic acid from Staphylococcus aureus induce tumor necrosis factor alpha, interleukin 6 (IL-6), and IL-10 production in both T cells and monocytes in a human whole blood model. Infect. Immun. 68 (2000) 3965–3670. CrossrefGoogle Scholar

  • [41] Ellingsen, E., Morath, S., Flo, T., Schromm, A., Hartung, T., Thiemermann, C., Espevik, T., Golenbock, D., Foster, D., Solberg, R., Aasen, A. and Wang, J. Induction of cytokine production in human T cells and monocytes by highly purified lipoteichoic acid: involvement of Toll-like receptors and CD14. Med. Sci. Monit. 8 (2002) BR149–156. Google Scholar

  • [42] Wang, J.P., Kurt-Jones, E.A., Shin, O.S., Manchak, M.D., Levin, M.J. and Finberg, R.W. Varicella-zoster virus activates inflammatory cytokines in human monocytes and macrophages via Toll-like receptor 2. J. Virol. 79 (2005) 12658–12666. CrossrefGoogle Scholar

  • [43] Smith, M.F.Jr, Mitchell, A., Li, G., Ding, S., Fitzmaurice, A.M., Ryan, K., Crowe, S. and Goldberg, J.B. Toll-like receptor (TLR) 2 and TLR5, but not TLR4, are required for Helicobacter pylori-induced NF-kappa B activation and chemokine expression by epithelial cells. J. Biol. Chem. 278 (2003) 32552–32560. Google Scholar

  • [44] Gaudreault, E., Fiola, S., Olivier, M. and Gosselin, J. Epstein-Barr virus induces MCP-1 secretion by human monocytes via TLR2. J. Virol. 81 (2007) 8016–8024. Google Scholar

  • [45] Hertz, C.J., Wu, Q., Porter, E.M., Zhang, Y.J., Weismuller, K.H., Godowski, P.J., Ganz, T., Randell, S.H. and Modlin, R.L. Activation of Toll-like receptor 2 on human tracheobronchial epithelial cells induces the antimicrobial peptide human beta defensin-2. J. Immunol. 171 (2003) 6820–6826. Google Scholar

  • [46] Alexopolou, L., Holt, A.C., Medzhitov, R. and Flavell, R.A. Recognition of double-stranded RNA and activation of NF-κB by toll-like receptor 3. Nature 413 (2001) 732–738. Google Scholar

  • [47] Guillot, L., Le Goffic, R., Bloch, S., Escriou, N., Akira, S., Chignard, M. and Si-Tahar, M. Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus. J. Biol. Chem. 280 (2005) 5571–5580. Google Scholar

  • [48] Li, Q., Withoff, S. and Verma, I.M. Inflammation-associated cancer: NF-kappaB is the lynchpin. Trends Immunol. 26 (2005) 318–325. CrossrefGoogle Scholar

  • [49] Balkwill, F. and Coussens, L.M. Cancer: an inflammatory link. Nature 431 (2004) 405–406. Google Scholar

  • [50] Gupta, R.A. and Dubois, R.N. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat. Rev. Cancer 1 (2001) 11–21. CrossrefGoogle Scholar

  • [51] Robak, P., Smolewski, P. and Robak, T. The role of non-steroidal anti-inflammatory drugs in the risk of development and treatment of hematologic malignancies. Leuk. Lymphoma 49 (2008) 1452–1462. CrossrefGoogle Scholar

  • [52] Pikarsky, E., Porat, R.M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E. and Ben-Neriah, Y. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431 (2004) 461–466. Google Scholar

  • [53] Palayoor, S.T., Youmell, M.Y., Calderwood, S.K., Coleman, C.N. and Price, B.D. Constitutive activation of IkappaB kinase alpha and NF-kappaB in prostate cancer cells is inhibited by ibuprofen. Oncogene 18 (1999) 7389–7394. CrossrefGoogle Scholar

  • [54] Baron, F., Turhan, A.G., Giron-Michel, J., Azzarone, B., Bentires-Alj, M., Bours, V., Bourhis, J.H., Chouaib, S. and Caignard, A. Leukemic target susceptibility to natural killer cytotoxicity: relationship with BCR-ABL expression. Blood 99 (2002) 2107–2113. CrossrefGoogle Scholar

  • [55] Griffin, J.D. Leukemia stem cells and constitutive activation of NF-kappaB. Blood 98 (2001) 2291. CrossrefGoogle Scholar

  • [56] Feinman, R., Koury, J., Thames, M., Barlogie, B., Epstein, J. and Siegel, D.S. Role of NF-kappaB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2. Blood 93 (1999) 3044–3052. Google Scholar

  • [57] Philip, M., Rowley, D.A. and Schreiber, H. Inflammation as a tumor promoter in cancer induction. Semin. Cancer Biol. 14 (2004) 433–439. CrossrefGoogle Scholar

  • [58] Chang, Y.J., Wu, M.S., Lin, J.T. and Chen, C.C. Helicobacter pylori-induced invasion and angiogenesis of gastric cells is mediated by cyclooxygenase-2 induction through TLR2/TLR9 and promoter regulation. J. Immunol. 175 (2005) 8242–8252. Google Scholar

  • [59] Li, V.W., Li, W.W., Talcott, K.E. and Zhai, A.W. Imiquimod as an antiangiogenic agent. J. Drugs Dermatol. 4 (2005) 708–717. Google Scholar

  • [60] Majewski, S., Marczak, M., Mlynarczyk, B., Benninghoff, B. and Jablonska, S. Imiquimod is a strong inhibitor of tumor cell-induced angiogenesis. Int. J. Dermatol. 44 (2005) 14–19. CrossrefGoogle Scholar

  • [61] Damiano, V., Caputo, R., Bianco, R., D’Armiento, F.P., Leonardi, A., De Placido, S., Bianco, A.R., Agrawal, S., Ciardiello, F. and Tortora, G. Novel toll-like receptor 9 agonist induces epidermal growth factor receptor (EGFR) inhibition and synergistic antitumor activity with EGFR inhibitors. Clin. Cancer Res. 12 (2006) 577–583. CrossrefGoogle Scholar

  • [62] Fukata, M., Chen, A., Vamadevan, A.S., Cohen, J., Breglio, K., Krishnareddy, S., Hsu, D., Xu, R., Harpaz, N., Dannenberg, A.J., Subbaramaiah, K., Cooper, H.S., Itzkowitz, S.H. and Abreu, M.T. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology 133 (2007) 1869–1881. Google Scholar

  • [63] Swann, J.B., Vesely, M.D., Silva, A., Sharkey, J., Akira, S., Schreiber, R.D. and Smyth, M.J. Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc. Natl. Acad. Sci. USA 105 (2008) 652–656. CrossrefGoogle Scholar

  • [64] Kundu, S.D., Leem, C., Billips, B.K., Habermacher, G.M., Zhang, Q., Liu, V., Wong, L.Y., Klumpp, D.J. and Thumbikat, P. The toll-like receptor pathway: a novel mechanism of infection-induced carcinogenesis of prostate epithelial cells. Prostate 68 (2008) 223–229. CrossrefGoogle Scholar

  • [65] Pries, R., Hogrefe, L., Xie, L., Frenzel, H., Brocks, C., Ditz, C. and Wollenberg, B. Induction of c-Myc-dependent cell proliferation through toll-like receptor 3 in head and neck cancer. Int. J. Mol. Med. 21 (2008) 209–215. Google Scholar

  • [66] Jego, G., Bataille, R., Geffroy-Luseau, A., Descamps, G. and Pellat-Deceunynck, C. Pathogen-associated molecular patterns are growth and survival factors for human myeloma cells through Toll-like receptors. Leukemia 20 (2006) 1130–1137. CrossrefGoogle Scholar

  • [67] Chochi, K., Ichikura, T., Kinoshita, M., Majima, T., Shinomiya, N., Tsujimoto, H., Kawabata, T., Sugasawa, H., Ono, S., Seki, S. and Mochizuki, H. Helicobacter pylori augments growth of gastric cancers via the lipopolysaccharide-toll-like receptor 4 pathway whereas its lipopolysaccharide attenuates antitumor activities of human mononuclear cells. Clin. Cancer Res. 14 (2008) 2909–2917. CrossrefGoogle Scholar

  • [68] Paone, A., Starace, D., Galli, R., Padula, F., De Cesaris, P., Filippini, A., Ziparo, E. and Riccioli, A. Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis 29 (2008) 1334–1342. CrossrefGoogle Scholar

  • [69] Barnhart, B.C. and Peter, M.E. The TNF receptor 1: a split personality complex. Cell 114 (2003) 148–150. CrossrefGoogle Scholar

  • [70] Jahrsdörfer, B., Wooldridge, J.E., Blackwell, S.E., Taylor, C.M., Griffith, T.S., Link, B.K. and Weiner, G.J. Immunostimulatory oligodeoxynucleotides induce apoptosis of B cell chronic lymphocytic leukemia cells. J. Leukoc. Biol. 77 (2005) 378–387. Google Scholar

  • [71] Jahrsdörfer, B., Jox, R., Mühlenhoff, L., Tschoep, K., Krug, A., Rothenfusser, S., Meinhardt, G., Emmerich, B., Endres, S. and Hartmann, G. Modulation of malignant B cell activation and apoptosis by bcl-2 antisense ODN and immunostimulatory CpG ODN. J. Leukoc. Biol. 72 (2002) 83–92. Google Scholar

  • [72] Smits, E.L., Ponsaerts, P., Van de Velde, A.L., Van Driessche, A., Cools, N., Lenjou, M., Nijs, G., Van Bockstaele, D.R., Berneman, Z.N. and Van Tendeloo, V.F. Proinflammatory response of human leukemic cells to dsRNA transfection linked to activation of dendritic cells. Leukemia 21 (2007) 1691–1699. CrossrefGoogle Scholar

  • [73] Salaun, B., Lebecque, S., Matikainen, S., Rimoldi, D. and Romero, P. Toll-like receptor 3 expressed by melanoma cells as a target for therapy? Clin. Cancer Res. 13 (2007) 4565–4574. CrossrefGoogle Scholar

  • [74] Lehner, M., Bailo, M., Stachel, D., Roesler, W., Parolini, O. and Holter, W. Caspase-8 dependent apoptosis induction in malignant myeloid cells by TLR stimulation in the presence of IFN-alpha. Leuk. Res. 31 (2007) 1729–1735. CrossrefGoogle Scholar

  • [75] Haase, R., Kirschning, C.J., Sing, A., Schröttner, P., Fukase, K., Kusumoto, S., Wagner, H., Heesemann, J. and Ruckdeschel, K. A dominant role of Toll-like receptor 4 in the signaling of apoptosis in bacteria-faced macrophages. J. Immunol. 171 (2003) 4294–4303. Google Scholar

  • [76] Hsu, L.C., Park, J.M., Zhang, K., Luo, J.L., Maeda, S., Kaufman, R.J., Eckmann, L., Guiney, D.G. and Karin, M. The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4. Nature 428 (2004) 341–345. Google Scholar

  • [77] Into, T., Kiura, K., Yasuda, M., Kataoka, H., Inoue, N., Hasebe, A., Takeda, K., Akira, S. and Shibata, K. Stimulation of human Toll-like receptor (TLR) 2 and TLR6 with membrane lipoproteins of Mycoplasma fermentans induces apoptotic cell death after NF-kappa B activation. Cell. Microbiol. 6 (2004) 187–199. Google Scholar

  • [78] Jung, D.Y., Lee, H., Jung, B.Y., Ock, J., Lee, M.S., Lee, W.H. and Suk, K. TLR4, but not TLR2, signals autoregulatory apoptosis of cultured microglia: a critical role of IFN-beta as a decision maker. J. Immunol. 174 (2005) 6467–6476. Google Scholar

  • [79] Ma, Y., Liu, H., Tu-Rapp, H., Thiesen, H.J., Ibrahim, S.M., Cole, S.M. and Pope, R.M. Fas ligation on macrophages enhances IL-1R1-Toll-like receptor 4 signaling and promotes chronic inflammation. Nat. Immunol. 5 (2004) 380–387. Google Scholar

  • [80] Imtiyaz, H.Z., Rosenberg, S., Zhang, Y., Rahman, Z.S., Hou, Y.J., Manser, T. and Zhang, J. The Fas-associated death domain protein is required in apoptosis and TLR-induced proliferative responses in B cells. J. Immunol. 176 (2006) 6852–6861. Google Scholar

  • [81] Kelly, M.G., Alvero, A.B., Chen, R., Silasi, D.A., Abrahams, V.M., Chan, S., Visintin, I., Rutherford, T. and Mor, G. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res. 66 (2006) 3859–3868. CrossrefGoogle Scholar

  • [82] Bottero, V., Busuttil, V., Loubat, A., Magné, N., Fischel, J.L., Milano, G. and Peyron, J.F. Activation of nuclear factor kappaB through the IKK complex by the topoisomerase poisons SN38 and doxorubicin: a brake to apoptosis in HeLa human carcinoma cells. Cancer Res. 61 (2001) 7785–7791. Google Scholar

  • [83] Tosi, P., Zinzani, P.L., Pellacani, A., Ottaviani, E., Magagnoli, M. and Tura, S. Loxoribine affects fludarabine activity on freshly isolated B-chronic lymphocytic leukemia cells. Leuk. Lymphoma 26 (1997) 343–348. Google Scholar

  • [84] Pellacani, A., Tosi, P., Zinzani, P.L., Ottaviani, E., Albertini, P., Magagnoli, M. and Tura, S. Cytotoxic combination of loxoribine with fludarabine and mafosfamide on freshly isolated B-chronic lymphocytic leukemia cells. Leuk. Lymphoma 33 (1999) 147–153. Google Scholar

  • [85] Shi, Y., White, D., He, L., Miller, R.L. and Spaner, D.E. Toll-like receptor-7 tolerizes malignant B cells and enhances killing by cytotoxic agents. Cancer Res. 67 (2007) 1823–1831. Google Scholar

  • [86] Garay, R.P., Viens, P., Bauer, J., Normier, G., Bardou, M., Jeannin, J.F. and Chiavaroli, C. Cancer relapse under chemotherapy: why TLR2/4 receptor agonists can help. Eur. J. Pharmacol. 563 (2007) 1–17. Google Scholar

  • [87] Coussens, L.M. and Werb, Z. Inflammation and cancer. Nature. 420 (2002) 860–867. Google Scholar

  • [88] Sakaguchi, S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22 (2004) 531–562. CrossrefGoogle Scholar

  • [89] Fisson, S., Darrasse-Jèze, G., Litvinova, E., Septier, F., Klatzmann, D., Liblau, R. and Salomon, B.L. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J. Exp. Med. 198 (2003) 737–746. Google Scholar

  • [90] Singh, B., Read, S., Asseman, C., Malmström, V., Mottet, C., Stephens, L.A., Stepankova, R., Tlaskalova, H. and Powrie, F. Control of intestinal inflammation by regulatory T cells. Immunol Rev. 182 (2001) 190–200. Google Scholar

  • [91] Hori, S., Carvalho, T.L. and Demengeot, J. CD25+CD4+ regulatory T cells suppress CD4+ T cell-mediated pulmonary hyperinflammation driven by Pneumocystis carinii in immunodeficient mice. Eur. J. Immunol. 32 (2002) 1282–1291. CrossrefGoogle Scholar

  • [92] Hänig, J. and Lutz, M.B. Suppression of mature dendritic cell function by regulatory T cells in vivo is abrogated by CD40 licensing. J. Immunol. 180 (2008) 1405–1413. CrossrefGoogle Scholar

  • [93] Caramalho, I., Lopes-Carvalho, T., Ostler, D., Zelenay, S., Haury, M. and Demengeot, J. Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J. Exp. Med. 197 (2003) 403–411. Google Scholar

  • [94] Sfondrini, L., Rossini, A., Besusso, D., Merlo, A., Tagliabue, E., Mènard, S. and Balsari, A. Antitumor activity of the TLR-5 ligand flagellin in mouse models of cancer. J. Immunol. 176 (2006) 6624–6630. Google Scholar

  • [95] Peng, G., Guo, Z., Kiniwa, Y., Voo, K.S., Peng, W., Fu, T., Wang, D.Y., Li, Y., Wang, H.Y. and Wang, R.F. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309 (2005) 1380–1384. Google Scholar

  • [96] Cella, M., Salio, M., Sakakibara, Y., Langen, H., Julkunen, I. and Lanzavecchia, A. Maturation, activation, and protection of dendritic cells induced by double-stranded RNA. J. Exp. Med. 189 (1999) 821–829. Google Scholar

  • [97] Pulendran, B., Kumar, P., Cutler, W., Mohamadzadeh, M., Van Dyke, T. and Banchereau, J. Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo. J. Immunol. 167 (2001) 5067–5076. Google Scholar

  • [98] Pasare, C. and Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299 (2003) 1033–1036. Google Scholar

  • [99] Spaner, D.E., Shi, Y., White, D., Mena, J., Hammond, C., Tomic, J., He, L., Tomai, M.A., Miller, R.L., Booth, J. and Radvanyi, L. Immunomodulatory effects of Toll-like receptor-7 activation on chronic lymphocytic leukemia cells. Leukemia 20 (2006) 286–295. Google Scholar

  • [100] Tomic, J., White, D., Shi, Y., Mena, J., Hammond, C., He, L., Miller, R.L. and Spaner, D.E. Sensitization of IL-2 signaling through TLR-7 enhances B lymphoma cell immunogenicity. J. Immunol. 176 (2006) 3830–3839. Google Scholar

  • [101] Decker, T., Schneller, F., Sparwasser, T., Tretter, T., Lipford, G.B., Wagner, H. and Peschel, C. Immunostimulatory CpG-oligonucleotides cause proliferation, cytokine production, and an immunogenic phenotype in chronic lymphocytic leukemia B cells. Blood 95 (2000) 999–1006. Google Scholar

  • [102] Decker, T., Schneller, F., Kronschnabl, M., Dechow, T., Lipford, G.B., Wagner, H. and Peschel, C. Immunostimulatory CpG-oligonucleotides induce functional high affinity IL-2 receptors on B-CLL cells: costimulation with IL-2 results in a highly immunogenic phenotype. Exp. Hematol. 28 (2000) 558–568. CrossrefGoogle Scholar

  • [103] Decker, T., Hipp, S., Kreitman, R.J., Pastan, I., Peschel, C., Licht, T. Sensitization of B-cell chronic lymphocytic leukemia cells to recombinant immunotoxin by immunostimulatory phosphorothioate oligodeoxynucleotides. Blood 99 (2002) 1320–1326. Google Scholar

  • [104] Evel-Kabler, K., Song, X.T., Aldrich, M., Huang, X.F. and Chen, S.Y. SOCS1 restricts dendritic cells’ ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling. J. Clin. Invest. 116 (2006) 90–100. Google Scholar

  • [105] Tormo, D., Ferrer, A., Bosch, P., Gaffal, E., Basner-Tschakarjan, E., Wenzel, J. and Tüting, T. Therapeutic efficacy of antigen-specific vaccination and toll-like receptor stimulation against established transplanted and autochthonous melanoma in mice. Cancer Res. 66 (2006) 5427–5435. CrossrefGoogle Scholar

  • [106] Wysocka, M., Benoit, B.M., Newton, S., Azzoni, L., Montaner, L.J. and Rook, A.H. Enhancement of the host immune responses in cutaneous T-cell lymphoma by CpG oligodeoxynucleotides and IL-15. Blood 104 (2004) 4142–4149. CrossrefGoogle Scholar

  • [107] Mangsbo, S.M., Ninalga, C., Essand, M., Loskog, A. and Tötterman, T.H. CpG therapy is superior to BCG in an orthotopic bladder cancer model and generates CD4+ T-cell immunity. J. Immunother. 31 (2008) 34–42. http://dx.doi.org/10.1097/CJI.0b013e3181587d29CrossrefGoogle Scholar

  • [108] Ren, T., Wen, Z.K., Liu, Z.M., Qian, C., Liang, Y.J., Jin, M.L., Cai, Y.Y. and Xu, L. Targeting toll-like receptor 9 with CpG oligodeoxynucleotides enhances anti-tumor responses of peripheral blood mononuclear cells from human lung cancer patients. Cancer Invest. 26 (2008) 448–455. CrossrefGoogle Scholar

  • [109] Roda, J.M., Parihar, R. and Carson, W.E.3rd. CpG-containing oligodeoxynucleotides act through TLR9 to enhance the NK cell cytokine response to antibody-coated tumor cells. J. Immunol. 175 (2005) 1619–1627. Google Scholar

  • [110] Frankenberger, M., Pechumer, H. and Ziegler-Heitbrock, H.W. Interleukin-10 is upregulated in LPS tolerance. J. Inflamm. 45 (1995) 56–63. Google Scholar

  • [111] Tominaga, K., Saito, S., Matsuura, M. and Nakano, M. Lipopolysaccharide tolerance in murine peritoneal macrophages induces downregulation of the lipopolysaccharide signal transduction pathway through mitogen-activated protein kinase and nuclear factor-kappaB cascades, but not lipopolysaccharide-incorporation steps. Biochim. Biophys. Acta 1450 (1999) 130–144. Google Scholar

  • [112] Medvedev, A.E., Kopydlowski, K.M. and Vogel, S.N. Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages: dysregulation of cytokine, chemokine, and toll-like receptor 2 and 4 gene expression. J. Immunol. 164 (2000) 5564–5574. Google Scholar

  • [113] Nomura, F., Akashi, S., Sakao, Y., Sato, S., Kawai, T., Matsumoto, M., Nakanishi, K., Kimoto, M., Miyake, K., Takeda, K. and Akira, S. Cutting edge: endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface toll-like receptor 4 expression. J. Immunol. 164 (2000) 3476–3479. Google Scholar

  • [114] Hume, D.A., Underhill, D.M., Sweet, M.J., Ozinsky, A.O., Liew, F.Y. and Aderem, A. Macrophages exposed continuously to lipopolysaccharide and other agonists that act via toll-like receptors exhibit a sustained and additive activation state. BMC Immunol. 2 (2001) 11. CrossrefGoogle Scholar

  • [115] Randow, F., Syrbe, U., Meisel, C., Krausch, D., Zuckermann, H., Platzer, C. and Volk, H.D. Mechanism of endotoxin desensitization: involvement of interleukin 10 and transforming growth factor beta. J. Exp. Med. 181 (1995) 1887–1892. Google Scholar

  • [116] Hamdy, S., Molavi, O., Ma, Z., Haddadi, A., Alshamsan, A., Gobti, Z., Elhasi, S., Samuel, J. and Lavasanifar, A. Co-delivery of cancer-associated antigen and Toll-like receptor 4 ligand in PLGA nanoparticles induces potent CD8(+) T cell-mediated anti-tumor immunity. Vaccine 26 (2008) 5046–5057. CrossrefGoogle Scholar

  • [117] Ramakrishna, V., Vasilakos, J.P., Tario, J.D.Jr, Berger, M.A., Wallace, P.K. and Keler, T. Toll-like receptor activation enhances cell-mediated immunity induced by an antibody vaccine targeting human dendritic cells. J. Transl. Med. 5 (2007) 5. CrossrefGoogle Scholar

  • [118] den Brok, M.H., Sutmuller, R.P., Nierkens, S., Bennink, E.J., Toonen, L.W., Figdor, C.G., Ruers, T.J. and Adema, G.J. Synergy between in situ cryoablation and TLR9 stimulation results in a highly effective in vivo dendritic cell vaccine. Cancer Res. 66 (2006) 7285–7292. CrossrefGoogle Scholar

  • [119] Koido, S., Hara, E., Homma, S., Torii, A., Toyama, Y., Kawahara, H., Watanabe, M., Yanaga, K., Fujise, K., Tajiri, H., Gong, J. and Toda, G. Dendritic cells fused with allogeneic colorectal cancer cell line present multiple colorectal cancer-specific antigens and induce antitumor immunity against autologous tumor cells. Clin. Cancer Res. 11 (2005) 7891–7900. CrossrefGoogle Scholar

  • [120] Adams, S., O’Neill, D.W., Nonaka, D., Hardin, E., Chiriboga, L., Siu, K., Cruz, C.M., Angiulli, A., Angiulli, F., Ritter, E., Holman, R.M., Shapiro, R.L., Berman, R.S., Berner, N., Shao. Y., Manches, O., Pan, L., Venhaus, R.R., Hoffman, E.W., Jungbluth, A., Gnjatic, S., Old, L., Pavlick, A.C. and Bhardwaj, N. Immunization of malignant melanoma patients with fulllength NY-ESO-1 protein using TLR7 agonist imiquimod as vaccine adjuvant. J. Immunol. 181 (2008) 776–784. Google Scholar

  • [121] Lesimple, T., Neidhard, E.M., Vignard, V., Lefeuvre, C., Adamski, H., Labarrière, N., Carsin, A., Monnier, D., Collet, B., Clapissonm G., Birebent, B., Philip, I., Toujas, L., Chokri, M. and Quillien, V. Immunologic and clinical effects of injecting mature peptide-loaded dendritic cells by intralymphatic and intranodal routes in metastatic melanoma patients. Clin. Cancer Res. 12 (2006) 7380–7388. CrossrefGoogle Scholar

  • [122] Speiser, D.E., Liénard, D., Rufer, N., Rubio-Godoy, V., Rimoldi, D., Lejeune, F., Krieg, A.M., Cerottini, J.C. and Romero, P. Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J. Clin. Invest. 115 (2005) 739–746. Google Scholar

  • [123] Shackleton, M., Davis, I.D., Hopkins, W., Jackson, H., Dimopoulos, N., Tai, T., Chen, Q., Parente, P., Jefford, M., Masterman, K.A., Caron, D., Chen, W., Maraskovsky, E. and Cebon, J. 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 (2004) 9. Google Scholar

  • [124] Manegold, C., Gravenor, D., Woytowitz, D., Mezger, J., Hirsh, V., Albert, G., Al-Adhami, M., Readett, D., Krieg, A.M. and Leichman, C.G. Randomized phase II trial of a toll-like receptor 9 agonist oligodeoxynucleotide, PF-3512676, in combination with first-line taxane plus platinum chemotherapy for advanced-stage non-small-cell lung cancer. J. Clin. Oncol. 26 (2008) 3979–3986. Google Scholar

  • [125] Dummer, R., Hauschild, A., Becker, J.C., Grob, J.J., Schadendorf, D., Tebbs, V., Skalsky, J., Kaehler, K.C., Moosbauer, S., Clark, R., Meng, T.C. and Urosevic, M. An exploratory study of systemic administration of the toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma. Clin. Cancer Res. 14 (2008) 856–864. Google Scholar

  • [126] Pashenkov, M., Goëss, G., Wagner, C., Hörmann, M., Jandl, T., Moser, A., Britten, C.M., Smolle, J., Koller, S., Mauch, C., Tantcheva-Poor, I., Grabbe, S., Loquai, C., Esser, S., Franckson, T., Schneeberger, A., Haarmann, C., Krieg, A.M., Stingl, G. and Wagner, S.N. Phase II trial of a toll-like receptor 9-activating oligonucleotide in patients with metastatic melanoma. J. Clin. Oncol. 24 (2006) 5716–5724. CrossrefGoogle Scholar

  • [127] Schmidt, J., Welsch, T., Jäger, D, Mühlradt, P.F., Büchler, M.W., Märten, A. Intratumoural injection of the toll-like receptor-2/6 agonist ‘macrophage-activating lipopeptide-2’ in patients with pancreatic carcinoma: a phase I/II trial. Br. J. Cancer 97 (2007) 598–604. Google Scholar

  • [128] Link, B.K., Ballas, Z.K., Weisdorf, D., Wooldridge, J.E., Bossler, A.D., Shannon, M., Rasmussen, W.L., Krieg, A.M. and Weiner, G.J. Oligodeoxynucleotide CpG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin lymphoma. J. Immunother. 29 (2006) 558–568. Google Scholar

  • [129] Carpentier, A., Laigle-Donadey, F., Zohar, S., Capelle, L., Behin, A., Tibi, A., Martin-Duverneuil, N., Sanson, M., Lacomblez, L., Taillibert, S., Puybasset. L., Van Effenterre, R., Delattre, J.Y. and Carpentier, A.F. Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neuro- Oncol. 8 (2006) 60–66. Google Scholar

  • [130] Leonard, J.P., Link, B.K., Emmanouilides, C., Gregory, S.A., Weisdorf, D., Andrey, J., Hainsworth, J., Sparano, J.A., Tsai, D.E., Horning, S., Krieg, A.M. and Weiner, G.J. Phase I trial of toll-like receptor 9 agonist PF-3512676 with and following rituximab in patients with recurrent indolent and aggressive non Hodgkin’s lymphoma. Clin. Cancer Res. 13 (2007) 6168–6174. CrossrefGoogle Scholar

  • [131] Friedberg, J.W., Kim, H., McCauley, M., Hessel, E.M., Sims, P., Fisher, D.C., Nadler, L.M., Coffman, R.L. and Freedman, A.S. Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin lymphoma: increased interferon-alpha/beta-inducible gene expression, without significant toxicity. Blood 105 (2005) 489–495. Google Scholar

  • [132] Spaner, D.E., Miller, R.L., Mena, J., Grossman, L., Sorrenti, V. and Shi, Y. Regression of lymphomatous skin deposits in a chronic lymphocytic leukemia patient treated with the Toll-like receptor-7/8 agonist, imiquimod. Leuk. Lymphoma 46 (2005) 935–939. Google Scholar

About the article

Published Online: 2009-03-13

Published in Print: 2009-06-01


Citation Information: Cellular and Molecular Biology Letters, ISSN (Online) 1689-1392, DOI: https://doi.org/10.2478/s11658-008-0048-z.

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