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TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours

Abstract

Toll-like receptor (TLR) agonists are potent activators of innate immune responses, activating dendritic cell (DC) maturation and inflammatory cytokine secretion by innate immune cells and as a consequence they promote adaptive immune response when coadministered with foreign antigens. There is also some evidence from mouse models that TLR ligands can help to break tolerance to self-antigens and promote immune responses to tumour antigens. Therefore, they have been exploited as adjuvants for tumour vaccines or as immunotherapeutics against cancer. Clinical evaluation of TLR agonists has resulted in a licensed immunotherapeutic for basal cell carcinoma, but there have also been disappointing results from clinical trials, with one pharmaceutical company recently halting its clinical programme. A major obstacle to the development of any active immunotherapeutic approach to cancer is the immunosuppressive environment of the growing tumour, including the induction of tolerogenic DCs and regulatory T (Treg) cells, which suppress the development of protective effector T-cell responses. This can be compounded by the use of TLR ligands as immunotherapeutics. A problem with TLR agonists that has not been fully appreciated is that they can generate suppressive as well as inflammatory responses in innate immune cells and can promote the induction of regulatory as well as effector T cells. This is part of a normal mechanism for limiting collateral damage during infection or sterile inflammation, but can constrain their ability to induce protective antitumour immunity, especially in the immune suppressed environment of the tumour. Alternatively, manipulating the TLR-activated innate immune responses to selectively blocking immunosuppressive arm, as well as that induced by the tumour, may hold the key to enhancing their efficacy as tumour immunotherapeutics and as adjuvants for cancer vaccines.

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Abbreviations

Cox2:

cyclooxygenase-2

CTL:

cytotoxic T-lymphocytes

DC:

dendritic cell

HSP:

heat-shock protein

IDO:

indoleamine 2-3 dioxygenase

PAMP:

pathogen-associated molecular pattern

PGE2:

prostaglandin E2

TLR:

Toll-like receptor

Treg cell:

regulatory T cell

References

  • Agrawal S, Agrawal A, Doughty B, Gerwitz A, Blenis J, Van Dyke T et al. (2003). Cutting edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase–mitogen-activated protein kinase and c-Fos. J Immunol 171: 4984–4989.

    CAS  Google Scholar 

  • Akdis CA, Kussebi F, Pulendran B, Akdis M, Lauener RP, Schmidt-Weber CB et al. (2003). Inhibition of T helper 2-type responses, IgE production and eosinophilia by synthetic lipopeptides. Eur J Immunol 33: 2717–2726.

    CAS  Google Scholar 

  • Alvaro T, Lejeune M, Salvado MT, Bosch R, Garcia JF, Jaen J et al. (2005). Outcome in Hodgkin's lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res 11: 1467–1473.

    Google Scholar 

  • Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC et al. (2005). Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 23: 6043–6053.

    CAS  Google Scholar 

  • Banchereau J, Palucka AK . (2005). Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol 5: 296–306.

    CAS  Google Scholar 

  • Baratelli F, Lin Y, Zhu L, Yang SC, Heuze-Vourc'h N, Zeng G et al. (2005). Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. J Immunol 175: 1483–1490.

    CAS  Google Scholar 

  • Bellone G, Carbone A, Smirne C, Scirelli T, Buffolino A, Novarino A et al. (2006). Cooperative induction of a tolerogenic dendritic cell phenotype by cytokines secreted by pancreatic carcinoma cells. J Immunol 177: 3448–3460.

    CAS  Google Scholar 

  • Beutner KR, Geisse JK, Helman D, Fox TL, Ginkel A, Owens ML . (1999). Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream. J Am Acad Dermatol 41: 1002–1007.

    CAS  Google Scholar 

  • Boccaccio GL, Mor F, Steinman L . (1999). Non-coding plasmid DNA induces IFN-gamma in vivo and suppresses autoimmune encephalomyelitis. Int Immunol 11: 289–296.

    CAS  Google Scholar 

  • Bourquin C, Schreiber S, Beck S, Hartmann G, Endres S . (2006). Immunotherapy with dendritic cells and CpG oligonucleotides can be combined with chemotherapy without loss of efficacy in a mouse model of colon cancer. Int J Cancer 118: 2790–2795.

    CAS  Google Scholar 

  • Brandau S, Suttmann H . (2007). Thirty years of BCG immunotherapy for non-muscle invasive bladder cancer: a success story with room for improvement. Biomed Pharmacother 61: 299–305.

    CAS  Google Scholar 

  • Braun D, Longman RS, Albert ML . (2005). A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation. Blood 106: 2375–2381.

    CAS  Google Scholar 

  • Boyd AP, Ross PJ, Conroy H, Mahon N, Lavelle EC, Mills KH . (2005). Bordetella pertussis adenylate cyclase toxin modulates innate and adaptive immune responses: distinct roles for acylation and enzymatic activity in immunomodulation and cell death. J Immunol 175: 730–738.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Caron G, Duluc D, Fremaux I, Jeannin P, David C, Gascan H et al. (2005). Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-gamma production by memory CD4+ T cells. J Immunol 175: 1551–1557.

    CAS  Google Scholar 

  • Carreras J, Lopez-Guillermo A, Fox BC, Colomo L, Martinez A, Roncador G et al. (2006). High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood 108: 2957–2964.

    CAS  Google Scholar 

  • Chakraborty NG, Chattopadhyay S, Mehrotra S, Chhabra A, Mukherji B . (2004). Regulatory T-cell response and tumor vaccine-induced cytotoxic T lymphocytes in human melanoma. Hum Immunol 65: 794–802.

    CAS  Google Scholar 

  • Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N et al. (2003). Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198: 1875–1886.

    CAS  Google Scholar 

  • Chen Y, Zhang J, Moore SA, Ballas ZK, Portanova JP, Krieg AM et al. (2001). CpG DNA induces cyclooxygenase-2 expression and prostaglandin production. Int Immunol 13: 1013–1020.

    CAS  Google Scholar 

  • Cranmer LD, Trevor KT, Hersh EM . (2004). Clinical applications of dendritic cell vaccination in the treatment of cancer. Cancer Immunol Immunother 53: 275–306.

    Google Scholar 

  • Creagh EM, O'Neill LA . (2006). TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol 27: 352–357.

    CAS  Google Scholar 

  • Crellin NK, Garcia RV, Hadisfar O, Allan SE, Steiner TS, Levings MK . (2005). Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. J Immunol 175: 8051–8059.

    CAS  Google Scholar 

  • Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P et al. (2004). Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10: 942–949.

    CAS  Google Scholar 

  • Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P et al. (2003). Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 9: 562–567.

    CAS  Google Scholar 

  • Dannull J, Su Z, Rizzieri D, Yang BK, Coleman D, Yancey D et al. (2005). Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 115: 3623–3633.

    CAS  Google Scholar 

  • den Haan JM, Kraal G, Bevan MJ . (2007). Cutting edge: lipopolysaccharide induces IL-10-producing regulatory CD4+ T cells that suppress the CD8+ T cell response. J Immunol 178: 5429–5433.

    CAS  Google Scholar 

  • Dercamp C, Chemin K, Caux C, Trinchieri G, Vicari AP . (2005). Distinct and overlapping roles of interleukin-10 and CD25+ regulatory T cells in the inhibition of antitumor CD8 T-cell responses. Cancer Res 65: 8479–8486.

    CAS  Google Scholar 

  • Espenschied J, Lamont J, Longmate J, Pendas S, Wang Z, Diamond DJ et al. (2003). CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in an established murine tumor model. J Immunol 170: 3401–3407.

    CAS  Google Scholar 

  • Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R et al. (2003). Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 4: 1206–1212.

    CAS  Google Scholar 

  • Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF . (2004). Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172: 5149–5153.

    CAS  Google Scholar 

  • Foss FM . (2000). DAB(389)IL-2 (ONTAK): a novel fusion toxin therapy for lymphoma. Clin Lymphoma 1: 110–116; discussion 117.

    CAS  Google Scholar 

  • Frankel AE, Powell BL, Lilly MB . (2002). Diphtheria toxin conjugate therapy of cancer. Cancer Chemother Biol Response Modif 20: 301–313.

    CAS  Google Scholar 

  • Fricke I, Gabrilovich DI . (2006). Dendritic cells and tumor microenvironment: a dangerous liaison. Immunol Invest 35: 459–483.

    CAS  Google Scholar 

  • Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B et al. (2007). Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132: 2328–2339.

    Google Scholar 

  • Fujimoto S, Greene M, Sehon AH . (1975). Immunosuppressor T cells in tumor bearing host. Immunol Commun 4: 201–217.

    CAS  Google Scholar 

  • Gabrilovich DI, Ciernik IF, Carbone DP . (1996). Dendritic cells in antitumor immune responses. I. Defective antigen presentation in tumor-bearing hosts. Cell Immunol 170: 101–110.

    CAS  Google Scholar 

  • Garbi N, Arnold B, Gordon S, Hammerling GJ, Ganss R . (2004). CpG motifs as proinflammatory factors render autochthonous tumors permissive for infiltration and destruction. J Immunol 172: 5861–5869.

    CAS  Google Scholar 

  • Ghiringhelli F, Puig PE, Roux S, Parcellier A, Schmitt E, Solary E et al. (2005). Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med 202: 919–929.

    CAS  Google Scholar 

  • Gilboa E . (2007). DC-based cancer vaccines. J Clin Invest 117: 1195–1203.

    CAS  Google Scholar 

  • Golgher D, Jones E, Powrie F, Elliott T, Gallimore A . (2002). Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens. Eur J Immunol 32: 3267–3275.

    CAS  Google Scholar 

  • Groux H, O'Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE et al. (1997). A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389: 737–742.

    CAS  Google Scholar 

  • Hayashi T, Beck L, Rossetto C, Gong X, Takikawa O, Takabayashi K et al. (2004). Inhibition of experimental asthma by indoleamine 2,3-dioxygenase. J Clin Invest 114: 270–279.

    CAS  Google Scholar 

  • Heckelsmiller K, Beck S, Rall K, Sipos B, Schlamp A, Tuma E et al. (2002a). Combined dendritic cell- and CpG oligonucleotide-based immune therapy cures large murine tumors that resist chemotherapy. Eur J Immunol 32: 3235–3245.

    CAS  Google Scholar 

  • Heckelsmiller K, Rall K, Beck S, Schlamp A, Seiderer J, Jahrsdorfer B et al. (2002b). Peritumoral CpG DNA elicits a coordinated response of CD8 T cells and innate effectors to cure established tumors in a murine colon carcinoma model. J Immunol 169: 3892–3899.

    CAS  Google Scholar 

  • Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H et al. (2000). A Toll-like receptor recognizes bacterial DNA. Nature 408: 740–745.

    CAS  Google Scholar 

  • Higgins SC, Lavelle EC, McCann C, Keogh B, McNeela E, Byrne P et al. (2003). Toll-like receptor 4-mediated innate IL-10 activates antigen-specific regulatory T cells and confers resistance to Bordetella pertussis by inhibiting inflammatory pathology. J Immunol 171: 3119–3127.

    CAS  Google Scholar 

  • Hirahara K, Liu L, Clark RA, Yamanaka K, Fuhlbrigge RC, Kupper TS . (2006). The majority of human peripheral blood CD4+CD25highFoxp3+ regulatory T cells bear functional skin-homing receptors. J Immunol 177: 4488–4494.

    CAS  Google Scholar 

  • Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M et al. (2005). Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 65: 1089–1096.

    CAS  Google Scholar 

  • Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV et al. (2003). Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA 100: 4712–4717.

    CAS  Google Scholar 

  • Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, Taidi B et al. (1996). Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med 2: 52–58.

    CAS  Google Scholar 

  • Ichikawa HT, Williams LP, Segal BM . (2002). Activation of APCs through CD40 or Toll-like receptor 9 overcomes tolerance and precipitates autoimmune disease. J Immunol 169: 2781–2787.

    CAS  Google Scholar 

  • Inaba K, Inaba M, Romani N, Aya H, Deguchi M, Ikehara S et al. (1992). Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med 176: 1693–1702.

    CAS  Google Scholar 

  • Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N . (2002). Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 99: 12293–12297.

    CAS  Google Scholar 

  • Janeway Jr CA, Medzhitov R . (2002). Innate immune recognition. Annu Rev Immunol 20: 197–216.

    CAS  Google Scholar 

  • Jarnicki AG, Lysaght J, Todryk S, Mills KHG . (2006). Suppression of antitumor immunity by IL-10 and TGF-beta-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cell. J Immunol 177: 896–904.

    CAS  Google Scholar 

  • Jordan JT, Sun W, Hussain SF, Deangulo G, Prabhu SS, Heimberger AB . (2007). Preferential migration of regulatory T cells mediated by glioma-secreted chemokines can be blocked with chemotherapy. Cancer Immunol Immunother; e-pub ahead of print: 24 May 2007.

  • Kanzler H, Barrat FJ, Hessel EM, Coffman RL . (2007). Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat Med 13: 552–559.

    CAS  Google Scholar 

  • Karube K, Ohshima K, Tsuchiya T, Yamaguchi T, Kawano R, Suzumiya J et al. (2004). Expression of FoxP3, a key molecule in CD4CD25 regulatory T cells, in adult T-cell leukaemia/lymphoma cells. Br J Haematol 126: 81–84.

    CAS  Google Scholar 

  • Katakura K, Lee J, Rachmilewitz D, Li G, Eckmann L, Raz E . (2005). Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. J Clin Invest 115: 695–702.

    CAS  Google Scholar 

  • Kikkawa F, Kawai M, Oguchi H, Kojima M, Ishikawa H, Iwata M et al. (1993). Randomised study of immunotherapy with OK-432 in uterine cervical carcinoma. Eur J Cancer 29A: 1542–1546.

    CAS  Google Scholar 

  • Knutson KL, Disis ML . (2005). Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother 54: 721–728.

    CAS  Google Scholar 

  • Ko K, Yamazaki S, Nakamura K, Nishioka T, Hirota K, Yamaguchi T et al. (2005). Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. J Exp Med 202: 885–891.

    CAS  Google Scholar 

  • Korn T, Reddy J, Gao W, Bettelli E, Awasthi A, Petersen TR et al. (2007). Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat Med 13: 423–431.

    CAS  Google Scholar 

  • Kreitman RJ . (2004). Recombinant immunotoxins for the treatment of haematological malignancies. Expert Opin Biol Ther 4: 1115–1128.

    CAS  Google Scholar 

  • Krieg AM . (2006). Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 5: 471–484.

    CAS  Google Scholar 

  • Krieg AM . (2007). Development of TLR9 agonists for cancer therapy. J Clin Invest 117: 1184–1194.

    CAS  Google Scholar 

  • Kubo T, Hatton RD, Oliver J, Liu X, Elson CO, Weaver CT . (2004). Regulatory T cell suppression and anergy are differentially regulated by proinflammatory cytokines produced by TLR-activated dendritic cells. J Immunol 173: 7249–7258.

    CAS  Google Scholar 

  • Kudo-Saito C, Schlom J, Camphausen K, Coleman CN, Hodge JW . (2005). The requirement of multimodal therapy (vaccine, local tumor radiation, and reduction of suppressor cells) to eliminate established tumors. Clin Cancer Res 11: 4533–4544.

    CAS  Google Scholar 

  • Kwon ED, Hurwitz AA, Foster BA, Madias C, Feldhaus AL, Greenberg NM et al. (1997). Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer. Proc Natl Acad Sci USA 94: 8099–8103.

    CAS  Google Scholar 

  • Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD et al. (2005). IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201: 233–240.

    CAS  Google Scholar 

  • Lavelle EC, McNeela E, Armstrong ME, Leavy O, Higgins SC, Mills KH . (2003). Cholera toxin promotes the induction of regulatory T cells specific for bystander antigens by modulating dendritic cell activation. J Immunol 171: 2384–2392.

    CAS  Google Scholar 

  • Leach DR, Krummel MF, Allison JP . (1996). Enhancement of antitumor immunity by CTLA-4 blockade. Science 271: 1734–1736.

    CAS  Google Scholar 

  • Lin J, Zhang J, Dong X, Fang H, Chen J, Su N et al. (2006). Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: a phase I randomised controlled trial. Lancet 368: 991–997.

    CAS  Google Scholar 

  • Liu H, Komai-Koma M, Xu D, Liew FY . (2006). Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci USA 103: 7048–7053.

    CAS  Google Scholar 

  • Liu VC, Wong LY, Jang T, Shah AH, Park I, Yang X et al. (2007). Tumor evasion of the immune system by converting CD4+CD25− T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-beta. J Immunol 178: 2883–2892.

    CAS  Google Scholar 

  • Livingston PO . (1989). Experimental and clinical studies with active specific immunotherapy. Prog Clin Biol Res 288: 309–321.

    CAS  Google Scholar 

  • Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G et al. (2002). Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169: 2756–2761.

    CAS  Google Scholar 

  • Lizee G, Radvanyi LG, Overwijk WW, Hwu P . (2006). Improving antitumor immune responses by circumventing immunoregulatory cells and mechanisms. Clin Cancer Res 12: 4794–4803.

    CAS  Google Scholar 

  • Marshall NA, Christie LE, Munro LR, Culligan DJ, Johnston PW, Barker RN et al. (2004). Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 103: 1755–1762.

    CAS  Google Scholar 

  • McGuirk P, Mills KH . (2002). Pathogen-specific regulatory T cells provoke a shift in the Th1/Th2 paradigm in immunity to infectious diseases. Trends Immunol 23: 450–455.

    CAS  Google Scholar 

  • Mellor AL, Baban B, Chandler PR, Manlapat A, Kahler DJ, Munn DH . (2005). Cutting edge: CpG oligonucleotides induce splenic CD19+ dendritic cells to acquire potent indoleamine 2,3-dioxygenase-dependent T cell regulatory functions via IFN type 1 signaling. J Immunol 175: 5601–5605.

    CAS  Google Scholar 

  • Napolitani G, Rinaldi A, Bertoni F, Sallusto F, Lanzavecchia A . (2005). Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat Immunol 6: 769–776.

    CAS  Google Scholar 

  • Natarajan K, Latchumanan VK, Singh B, Singh S, Sharma P . (2003). Down-regulation of T helper 1 responses to mycobacterial antigens due to maturation of dendritic cells by 10-kDa mycobacterium tuberculosis secretory antigen. J Infect Dis 187: 914–928.

    CAS  Google Scholar 

  • Nava-Parada P, Forni G, Knutson KL, Pease LR, Celis E . (2007). Peptide vaccine given with a Toll-like receptor agonist is effective for the treatment and prevention of spontaneous breast tumors. Cancer Res 67: 1326–1334.

    CAS  Google Scholar 

  • Netea MG, Sutmuller R, Hermann C, Van der Graaf CA, Van der Meer JW, van Krieken JH et al. (2004). Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells. J Immunol 172: 3712–3718.

    CAS  Google Scholar 

  • North RJ . (1982). Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J Exp Med 155: 1063–1074.

    CAS  Google Scholar 

  • Obermeier F, Dunger N, Deml L, Herfarth H, Scholmerich J, Falk W . (2002). CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice. Eur J Immunol 32: 2084–2092.

    CAS  Google Scholar 

  • Oldenhove G, de Heusch M, Urbain-Vansanten G, Urbain J, Maliszewski C, Leo O et al. (2003). CD4+ CD25+ regulatory T cells control T helper cell type 1 responses to foreign antigens induced by mature dendritic cells in vivo. J Exp Med 198: 259–266.

    CAS  Google Scholar 

  • Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E . (1999). Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59: 3128–3133.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  • 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: 1380–1384.

    CAS  Google Scholar 

  • Peng G, Wang HY, Peng W, Kiniwa Y, Seo KH, Wang RF . (2007). Tumor-infiltrating gammadelta T cells suppress T and dendritic cell function via mechanisms controlled by a unique Toll-like receptor signaling pathway. Immunity 27: 334–348.

    CAS  Google Scholar 

  • Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ et al. (2003). Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100: 8372–8377.

    CAS  Google Scholar 

  • Pinzon-Charry A, Maxwell T, Lopez JA . (2005). Dendritic cell dysfunction in cancer: a mechanism for immunosuppression. Immunol Cell Biol 83: 451–461.

    CAS  Google Scholar 

  • Qian C, An H, Yu Y, Liu S, Cao X . (2007). TLR agonists induce regulatory dendritic cells to recruit Th1 cells via preferential IP-10 secretion and inhibit Th1 proliferation. Blood 109: 3308–3315.

    CAS  Google Scholar 

  • Reis e Sousa C . (2004). Activation of dendritic cells: translating innate into adaptive immunity. Curr Opin Immunol 16: 21–25.

    CAS  Google Scholar 

  • Ribas A, Camacho LH, Lopez-Berestein G, Pavlov D, Bulanhagui CA, Millham R et al. (2005). Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 23: 8968–8977.

    CAS  Google Scholar 

  • Ronaghy A, Prakken BJ, Takabayashi K, Firestein GS, Boyle D, Zvailfler NJ et al. (2002). Immunostimulatory DNA sequences influence the course of adjuvant arthritis. J Immunol 168: 51–56.

    CAS  Google Scholar 

  • Rosenberg SA, Yang JC, Restifo NP . (2004). Cancer immunotherapy: moving beyond current vaccines. Nat Med 10: 909–915.

    CAS  Google Scholar 

  • Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M . (1995). Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155: 1151–1164.

    CAS  Google Scholar 

  • Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F et al. (2005). Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102: 18538–18543.

    CAS  Google Scholar 

  • Schmidt C . (2007). Clinical setbacks for toll-like receptor 9 agonists in cancer. Nat Biotechnol 25: 825–826.

    CAS  Google Scholar 

  • Sfondrini L, Rossini A, Besusso D, Merlo A, Tagliabue E, Menard S et al. (2006). Antitumor activity of the TLR-5 ligand flagellin in mouse models of cancer. J Immunol 176: 6624–6630.

    CAS  Google Scholar 

  • Shimizu J, Yamazaki S, Sakaguchi S . (1999). Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163: 5211–5218.

    CAS  Google Scholar 

  • Smyth MJ, Godfrey DI . (2000). NKT cells and tumor immunity—a double-edged sword. Nat Immunol 1: 459–460.

    CAS  Google Scholar 

  • Smyth MJ, Godfrey DI, Trapani JA . (2001). A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol 2: 293–299.

    CAS  Google Scholar 

  • Somasundaram R, Jacob L, Swoboda R, Caputo L, Song H, Basak S et al. (2002). Inhibition of cytolytic T lymphocyte proliferation by autologous CD4+/CD25+ regulatory T cells in a colorectal carcinoma patient is mediated by transforming growth factor-beta. Cancer Res 62: 5267–5272.

    CAS  Google Scholar 

  • Speiser DE, Lienard D, Rufer N, Rubio-Godoy V, Rimoldi D, Lejeune F et al. (2005). Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J Clin Invest 115: 739–746.

    CAS  Google Scholar 

  • Srivastava PK . (2006). Therapeutic cancer vaccines. Curr Opin Immunol 18: 201–205.

    CAS  Google Scholar 

  • 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: 1441–1451.

    CAS  Google Scholar 

  • Sutmuller RP, den Brok MH, Kramer M, Bennink EJ, Toonen LW, Kullberg BJ et al. (2006). Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest 116: 485–494.

    CAS  Google Scholar 

  • Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP et al. (2001). Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 194: 823–832.

    CAS  Google Scholar 

  • Terness P, Bauer TM, Rose L, Dufter C, Watzlik A, Simon H et al. (2002). Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med 196: 447–457.

    CAS  Google Scholar 

  • Toka FN, Suvas S, Rouse BT . (2004). CD4+ CD25+ T cells regulate vaccine-generated primary and memory CD8+ T-cell responses against herpes simplex virus type 1. J Virol 78: 13082–13089.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Uehori J, Matsumoto M, Tsuji S, Akazawa T, Takeuchi O, Akira S et al. (2003). Simultaneous blocking of human Toll-like receptors 2 and 4 suppresses myeloid dendritic cell activation induced by Mycobacterium bovis bacillus Calmette–Guerin peptidoglycan. Infect Immun 71: 4238–4249.

    CAS  Google Scholar 

  • Valenti R, Huber V, Filipazzi P, Pilla L, Sovena G, Villa A et al. (2006). Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res 66: 9290–9298.

    CAS  Google Scholar 

  • Vicari AP, Chiodoni C, Vaure C, Ait-Yahia S, Dercamp C, Matsos F et al. (2002). Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med 196: 541–549.

    CAS  Google Scholar 

  • Viguier M, Lemaitre F, Verola O, Cho MS, Gorochov G, Dubertret L et al. (2004). Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol 173: 1444–1453.

    CAS  Google Scholar 

  • von Boehmer H . (2005). Mechanisms of suppression by suppressor T cells. Nat Immunol 6: 338–344.

    CAS  Google Scholar 

  • Watanabe Y, Iwa T . (1987). Clinical value of immunotherapy with the streptococcal preparation OK-432 in non-small cell lung cancer. J Biol Response Mod 6: 169–180.

    CAS  Google Scholar 

  • Weber J . (2007). Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist 12: 864–872.

    CAS  Google Scholar 

  • Wei S, Kryczek I, Zou L, Daniel B, Cheng P, Mottram P et al. (2005). Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res 65: 5020–5026.

    CAS  Google Scholar 

  • Whitmore MM, DeVeer MJ, Edling A, Oates RK, Simons B, Lindner D et al. (2004). Synergistic activation of innate immunity by double-stranded RNA and CpG DNA promotes enhanced antitumor activity. Cancer Res 64: 5850–5860.

    CAS  Google Scholar 

  • Wilson SB, Delovitch TL . (2003). Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity. Nat Rev Immunol 3: 211–222.

    CAS  Google Scholar 

  • Wolf D, Wolf AM, Rumpold H, Fiegl H, Zeimet AG, Muller-Holzner E et al. (2005). The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res 11: 8326–8331.

    CAS  Google Scholar 

  • Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G et al. (2001). Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 61: 4766–4772.

    CAS  Google Scholar 

  • Xu S, Koldovsky U, Xu M, Wang D, Fitzpatrick E, Son G et al. (2006). High-avidity antitumor T-cell generation by toll receptor 8-primed, myeloid-derived dendritic cells is mediated by IL-12 production. Surgery 140: 170–178.

    Google Scholar 

  • Yang Y, Huang CT, Huang X, Pardoll DM . (2004). Persistent Toll-like receptor signals are required for reversal of regulatory T cell-mediated CD8 tolerance. Nat Immunol 5: 508–515.

    CAS  Google Scholar 

  • Zeytin HE, Patel AC, Rogers CJ, Canter D, Hursting SD, Schlom J et al. (2004). Combination of a poxvirus-based vaccine with a cyclooxygenase-2 inhibitor (celecoxib) elicits antitumor immunity and long-term survival in CEA. Tg/MIN mice. Cancer Res 64: 3668–3678.

    CAS  Google Scholar 

  • Zhou G, Drake CG, Levitsky HI . (2006). Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines. Blood 107: 628–636.

    CAS  Google Scholar 

  • Zou W . (2005). Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5: 263–274.

    CAS  Google Scholar 

  • Zou W . (2006). Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6: 295–307.

    CAS  Google Scholar 

  • Zwaveling S, Ferreira Mota SC, Nouta J, Johnson M, Lipford GB, Offringa R et al. (2002). Established human papillomavirus type 16-expressing tumors are effectively eradicated following vaccination with long peptides. J Immunol 169: 350–358.

    CAS  Google Scholar 

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Conroy, H., Marshall, N. & Mills, K. TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours. Oncogene 27, 168–180 (2008). https://doi.org/10.1038/sj.onc.1210910

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