Skip to main content

Advertisement

SpringerLink
Log in

The extrinsic RNA-sensing pathway for adjuvant immunotherapy of cancer

  • Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Infection with RNA viruses presents a typical pattern of virus products, double-stranded RNA (dsRNA), and induces the maturation of antigen-presenting dendritic cell (mDC). There are several dsRNA sensors that are differentially distributed on the cell membrane and in the cytoplasm and are variably expressed depending on the cell type. Among these sensors, TLR3 links to the adaptor TICAM-1 (TRIF), which is characterized by its unique multipronged signaling cascades for cytokine/chemokine production, apoptosis and autophagy in both immune and tumor cells. In the context of mDC maturation, various cellular events are further induced in response to dsRNA; these include cross-priming followed by CD8+ CTL induction, NK activation and proliferation of CD4+ T cells including Th1, Th2, Treg and Th17 cells. In this review, we focus on the potential role of dsRNA in modulating the inflammatory milieu around mDCs and tumor-associated antigens to drive specific cellular effectors against the tumor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kono H, Rock KL (2008) How dying cells alert the immune system to danger. Nat Rev Immunol 8:279–289 (review)

    Article  PubMed  CAS  Google Scholar 

  2. Sheu BC, Chang WC, Cheng CY, Lin HH, Chang DY, Huang SC (2008) Cytokine regulation networks in the cancer microenvironment. Front Biosci 13:6255–6268 (review)

    Article  PubMed  CAS  Google Scholar 

  3. Melief CJM (2008) Cancer immunotherapy by dendritic cells. Immunity 29:372–383 (review)

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Steinman RM, Hemmi H (2006) Dendritic cells: translating innate to adaptive immunity. Curr Top Microbiol Immunol 311:17–58 (review)

    Article  PubMed  CAS  Google Scholar 

  6. Matsumoto M, Seya T (2008) TLR3: interferon induction by double-stranded RNA including poly(I:C). Adv Drug Deliv Rev 60:805–812 (review)

    Article  PubMed  CAS  Google Scholar 

  7. 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 413:732–738

    Article  PubMed  CAS  Google Scholar 

  8. Matsuo A, Oshiumi H, Tsujita T, Mitani H, Kasai H, Yoshimizu M, Matsumoto M, Seya T (2008) Teleost TLR22 recognizes RNA duplex to induce IFN and protect cells from birnaviruses. J Immunol 181:3474–3485

    PubMed  CAS  Google Scholar 

  9. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T (2004) The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5:730–737

    Article  PubMed  CAS  Google Scholar 

  10. Tanaka H, Samuel CE (1994) Mechanism of interferon action: structure of the mouse PKR gene encoding the interferon-inducible RNA-dependent protein kinase. Proc Natl Acad Sci USA 91:7995–7999

    Article  PubMed  CAS  Google Scholar 

  11. Kanneganti TD, Body-Malapel M, Amer A, Park JH, Whitfield J, Franchi L, Taraporewala ZF, Miller D, Patton JT, Inohara N, Núñez G (2006) Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J Biol Chem 281:36560–36568

    Article  PubMed  CAS  Google Scholar 

  12. Kanneganti TD, Ozören N, Body-Malapel M, Amer A, Park JH, Franchi L, Whitfield J, Barchet W, Colonna M, Vandenabeele P, Bertin J, Coyle A, Grant EP, Akira S, Núñez G (2006) Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440:233–236

    Article  PubMed  CAS  Google Scholar 

  13. Malathi K, Dong B, Gale M Jr, Silverman RH (2007) Small self-RNA generated by RNase L amplifies antiviral innate immunity. Nature 448:816–819

    Article  PubMed  CAS  Google Scholar 

  14. Wang RF, Miyahara Y, Wang HY (2008) Toll-like receptors and immune regulation: implications for cancer therapy. Oncogene 27:181–189 (review)

    Article  PubMed  Google Scholar 

  15. Seya T, Hazeki K, Inoue N, Matsumoto M. (2009) Pattern-recognition confers driving various cellular effectors on dendritic cells. Cancer Sci (in press) (review)

  16. Johnson CL, Gale M Jr (2006) CARD games between virus and host get a new player. Trends Immunol 27:1–4 (review)

    Article  PubMed  CAS  Google Scholar 

  17. Matsumoto M, Funami K, Tanabe M, Oshiumi H, Shingai M, Seto Y, Yamamoto A, Seya T (2003) Subcellular localization of Toll-like receptor 3 in human dendritic cells. J Immunol 171:3154–3162

    PubMed  CAS  Google Scholar 

  18. Sasai M, Shingai M, Funami K, Yoneyama M, Fujita T, Matsumoto M, Seya T (2006) NAK-associated protein 1 participates in both the TLR3 and the cytoplasmic pathways in type I IFN induction. J Immunol 177:8676–8683

    PubMed  CAS  Google Scholar 

  19. Ryzhakov G, Randow F (2007) SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK. EMBO J 26:3180–3190

    Article  PubMed  CAS  Google Scholar 

  20. Jounai N, Takeshita F, Kobiyama K, Sawano A, Miyawaki A, Xin KQ, Ishii KJ, Kawai T, Akira S, Suzuki K, Okuda K (2007) The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc Natl Acad Sci USA 104:14050–14055

    Article  PubMed  CAS  Google Scholar 

  21. Maire M, Parent R, Morand AL, Alotte C, Trépo C, Durantel D, Petit MA (2008) Characterization of the double-stranded RNA responses in human liver progenitor cells. Biochem Biophys Res Commun 368:556–562

    Article  PubMed  CAS  Google Scholar 

  22. Ermolaeva MA, Michallet MC, Papadopoulou N, Utermöhlen O, Kranidioti K, Kollias G, Tschopp J, Pasparakis M (2008) Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses. Nat Immunol 9:1037–1046

    Article  PubMed  CAS  Google Scholar 

  23. Matsumoto M, Kikkawa S, Kohase M, Miyake K, Seya T (2002) Establishment of a monoclonal antibody against human Toll-like receptor 3 that blocks double-stranded RNA-mediated signaling. Biochem Biophys Res Commun 293:1364–1369

    Article  PubMed  CAS  Google Scholar 

  24. Honda K, Taniguchi T (2006) IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol 6:644–658 (review)

    Article  PubMed  CAS  Google Scholar 

  25. Yang YL, Reis LF, Pavlovic J, Aguzzi A, Schäfer R, Kumar A, Williams BR, Aguet M, Weissmann C (1995) Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J 14:6095–6106

    PubMed  CAS  Google Scholar 

  26. Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, Foy E, Loo YM, Gale M Jr, Akira S, Yonehara S, Kato A, Fujita T (2005) Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol 175:2851–2858

    PubMed  CAS  Google Scholar 

  27. Pichlmair A, Schulz O, Tan CP, Näslund TI, Liljeström P, Weber F, Reis e Sousa C (2006) RIG-I-mediated antiviral responses to single-stranded RNA bearing 5’-phosphates. Science 314:997–1001

    Article  PubMed  CAS  Google Scholar 

  28. Hornung V, Ellegast J, Kim S, Brzózka K, Jung A, Kato H, Poeck H, Akira S, Conzelmann KK, Schlee M, Endres S, Hartmann G (2006) 5′-Triphosphate RNA is the ligand for RIG-I. Science 314:994–997

    Article  PubMed  Google Scholar 

  29. Saito T, Owen DM, Jiang F, Marcotrigiano J, Gale M Jr (2008) Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454:523–527

    Article  PubMed  CAS  Google Scholar 

  30. Absher M, Stinebring WR (1969) Toxic properties of a synthetic double-stranded RNA. Endotoxin-like properties of poly I. poly C, an interferon stimulator. Nature 223:715–717

    Article  PubMed  CAS  Google Scholar 

  31. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis e Sousa C, Matsuura Y, Fujita T, Akira S (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105

    Article  PubMed  CAS  Google Scholar 

  32. O’Neill LA, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7:353–364 (review)

    Article  PubMed  Google Scholar 

  33. Häcker H, Redecke V, Blagoev B, Kratchmarova I, Hsu LC, Wang GG, Kamps MP, Raz E, Wagner H, Häcker G, Mann M, Karin M (2006) Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439:204–207

    Article  PubMed  Google Scholar 

  34. Chen NJ, Chio II, Lin WJ, Duncan G, Chau H, Katz D, Huang HL, Pike KA, Hao Z, Su YW, Yamamoto K, de Pooter RF, Zúñiga-Pflücker JC, Wakeham A, Yeh WC, Mak TW (2008) Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors. Proc Natl Acad Sci USA 105:12429–12434

    Article  PubMed  CAS  Google Scholar 

  35. Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, Tschopp J (2004) RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat Immunol 5:503–507

    Article  PubMed  CAS  Google Scholar 

  36. Vanden Berghe T, van Loo G, Saelens X, Van Gurp M, Brouckaert G, Kalai M, Declercq W, Vandenabeele P (2004) Differential signaling to apoptotic and necrotic cell death by Fas-associated death domain protein FADD. J Biol Chem 279:7925–7933

    Article  Google Scholar 

  37. Meylan E, Tschopp J, Karin M (2006) Intracellular pattern recognition receptors in the host response. Nature 442:39–44 (review)

    Article  PubMed  CAS  Google Scholar 

  38. Honda K, Takaoka A, Taniguchi T (2006) Type I interferon gene induction by the interferon regulatory factor family of transcription factors. Immunity 25:349–360 (review)

    Article  PubMed  CAS  Google Scholar 

  39. Oshiumi H, Sasai M, Shida K, Fujita T, Matsumoto M, Seya T (2003) TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta. J Biol Chem 278:49751–49762

    Article  PubMed  CAS  Google Scholar 

  40. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O, Yoshimori T, Akira S (2008) Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456:264–268

    Article  PubMed  CAS  Google Scholar 

  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 4:161–167

    Article  PubMed  CAS  Google Scholar 

  42. Seya T, Matsumoto M, Ebihara T, Oshiumi H. (2003) Functional evolution of the TICAM-1 (TRIF) pathway for extrinsic RNA sensing. Immunol Rev (in press) (review)

  43. Funami K, Sasai M, Ohba Y, Oshiumi H, Seya T, Matsumoto M (2007) Spatiotemporal mobilization of Toll/IL-1 receptor domain-containing adaptor molecule-1 in response to dsRNA. J Immunol 179:6867–6872

    PubMed  CAS  Google Scholar 

  44. Funami K, Sasai M, Oshiumi H, Seya T, Matsumoto M (2008) Homo-oligomerization is essential for Toll/interleukin-1 receptor domain-containing adaptor molecule-1-mediated NF-kappaB and interferon regulatory factor-3 activation. J Biol Chem 283:18283–18291

    Article  PubMed  CAS  Google Scholar 

  45. Michallet MC, Meylan E, Ermolaeva MA, Vazquez J, Rebsamen M, Curran J, Poeck H, Bscheider M, Hartmann G, König M, Kalinke U, Pasparakis M, Tschopp J (2008) TRADD protein is an essential component of the RIG-like helicase antiviral pathway. Immunity 28:651–661

    Article  PubMed  CAS  Google Scholar 

  46. Foy E, Li K, Sumpter R Jr, Loo YM, Johnson CL, Wang C, Fish PM, Yoneyama M, Fujita T, Lemon SM, Gale M Jr (2005) Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Proc Natl Acad Sci USA 102:2986–2991

    Article  PubMed  CAS  Google Scholar 

  47. Rebsamen M, Meylan E, Curran J, Tschopp J (2008) The antiviral adaptor proteins Cardif and Trif are processed and inactivated by caspases. Cell Death Differ 15:1804–1811

    Article  PubMed  CAS  Google Scholar 

  48. Xu Y, Kim SO, Li Y, Han J (2006) Autophagy contributes to caspase-independent macrophage cell death. J Biol Chem 281:19179–19187

    Article  PubMed  CAS  Google Scholar 

  49. Shi CS, Kehrl JH (2008) MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. J Biol Chem 283:33175–33182

    Google Scholar 

  50. Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T (2006) TLR3 can directly trigger apoptosis in human cancer cells. J Immunol 176:4894–4901

    PubMed  CAS  Google Scholar 

  51. Zhou R, Wei H, Sun R, Tian Z (2007) Recognition of double-stranded RNA by TLR3 induces severe small intestinal injury in mice. J Immunol 178:4548–4556

    PubMed  CAS  Google Scholar 

  52. Han KJ, Su X, Xu LG, Bin LH, Zhang J, Shu HB (2004) Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways. J Biol Chem 279:15652–15661

    Article  PubMed  CAS  Google Scholar 

  53. McAllister CS, Samuel CE. (2008) Protein kinase PKR enhances the induction of interferon-beta and apoptosis mediated by cytoplasmic RNA sensors. J Biol Chem Nov 20. [Epub ahead of print]

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

    Article  PubMed  CAS  Google Scholar 

  55. Takeuchi O, Akira S (2007) Recognition of viruses by innate immunity. Immunol Rev 220:214–224 (review)

    Article  PubMed  CAS  Google Scholar 

  56. Lin ML, Zhan Y, Villadangos JA, Lew AM (2008) The cell biology of cross-presentation and the role of dendritic cell subsets. Immunol Cell Biol 86:353–362 (review)

    Article  PubMed  CAS  Google Scholar 

  57. Akazawa T, Masuda H, Saeki Y, Matsumoto M, Takeda K, Tsujimura K, Kuzushima K, Takahashi T, Azuma I, Akira S, Toyoshima K, Seya T (2004) Adjuvant-mediated tumor regression and tumor-specific cytotoxic response are impaired in MyD88-deficient mice. Cancer Res 64:757–764

    Article  PubMed  CAS  Google Scholar 

  58. Shen H, Tesar BM, Walker WE, Goldstein DR (2008) Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation. J Immunol 181:1849–1858

    PubMed  CAS  Google Scholar 

  59. Ebihara T, Matsumoto M, Seya T (2009) NK cell licensing by dendritic cell in RNA virus infection. Curr Immunol Rev (in press) (review)

  60. Akazawa T, Ebihara T, Okuno M, Okuda Y, Shingai M, Tsujimura K, Takahashi T, Ikawa M, Okabe M, Inoue N, Okamoto-Tanaka M, Ishizaki H, Miyoshi J, Matsumoto M, Seya T (2007) Antitumor NK activation induced by the Toll-like receptor 3-TICAM–1 (TRIF) pathway in myeloid dendritic cells. Proc Natl Acad Sci USA 104:252–257

    Article  PubMed  CAS  Google Scholar 

  61. Janssen EM, Lemmens EE, Wolfe T, Christen U, Von Herrath MG, Schoenberger SP (2003) CD4(+) T cells are required for secondary expansion and memory in CD8(+) T lymphocytes. Nature 421:852–856

    Article  PubMed  CAS  Google Scholar 

  62. Shedlock DJ, Shen H (2003) Requirement for CD4 T cell help in generating functional CD8T cell memory. Science 300:337–339

    Article  PubMed  CAS  Google Scholar 

  63. Sun JC, Bevan MJ (2003) Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300:339–342

    Article  PubMed  CAS  Google Scholar 

  64. Kumar H, Koyama S, Ishii KJ, Kawai T, Akira S (2008) Cutting edge: cooperation of IPS-1- and TRIF-dependent pathways in polyIC-enhanced antibody production and cytotoxic T cell responses. J Immunol 180:683–687

    PubMed  CAS  Google Scholar 

  65. Hou B, Reizis B, DeFranco AL (2008) Toll-like receptors activate innate and adaptive immunity by using dendritic cell-intrinsic and -extrinsic mechanisms. Immunity 29:272–282

    Article  PubMed  CAS  Google Scholar 

  66. Hamilton SE, Wolkers MC, Schoenberger SP, Jameson SC (2006) The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+ T cells. Nat Immunol 7:475–481

    Article  PubMed  CAS  Google Scholar 

  67. Yamaguchi T, Hirota K, Nagahama K, Ohkawa K, Takahashi T, Nomura T, Sakaguchi S (2007) Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity 27:145–159

    Article  PubMed  CAS  Google Scholar 

  68. Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanahan T, Kastelein RA, Oft M (2006) IL-23 promotes tumour incidence and growth. Nature 442:461–465

    Article  PubMed  CAS  Google Scholar 

  69. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor T-bet, directs Th1 lineage commitment. Cell 100:655–669

    Article  PubMed  CAS  Google Scholar 

  70. Bohnenkamp HR, Papazisis KT, Burchell JM, Taylor-Papadimitriou J (2007) Synergism of Toll-like receptor-induced interleukin-12p70 secretion by monocyte-derived dendritic cells is mediated through p38 MAPK and lowers the threshold of T-helper cell type 1 responses. Cell Immunol 247:72–84

    Article  PubMed  CAS  Google Scholar 

  71. Kuo CT, Leiden JM (1999) Transcriptional regulation of T-lymphocyte development and function. Annu Rev Immunol 17:149–187 (review)

    Article  PubMed  CAS  Google Scholar 

  72. Pasare C, Medzhitov R (2005) Control of B-cell responses by Toll-like receptors. Nature 438:364–368

    Article  PubMed  CAS  Google Scholar 

  73. Gavin AL, Hoebe K, Duong B, Ota T, Martin C, Beutler B, Nemazee D (2006) Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science 314:1936–1938

    Article  PubMed  CAS  Google Scholar 

  74. Mami-Chouaib F, Echchakir H, Dorothée G, Vergnon I, Chouaib S (2002) Antitumor cytotoxic T-lymphocyte response in human lung carcinoma: identification of a tumor-associated antigen. Immunol Rev 188:114–121 (review)

    Article  PubMed  CAS  Google Scholar 

  75. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123–1132

    Article  PubMed  CAS  Google Scholar 

  76. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141

    Article  PubMed  CAS  Google Scholar 

  77. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17(+) T helper cells. Cell 126:1121–1133

    Article  PubMed  CAS  Google Scholar 

  78. Langowski JL, Kastelein RA, Oft M (2007) Swords into plowshares: IL-23 repurposes tumor immune surveillance. Trends Immunol 28:207–212 (review)

    Article  PubMed  CAS  Google Scholar 

  79. Shime H, Yabu M, Akazawa T, Kodama K, Matsumoto M, Seya T, Inoue N (2008) Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway. J Immunol 180:7175–7183

    PubMed  CAS  Google Scholar 

  80. Guo B, Chang EY, Cheng G (2008) The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. J Clin Invest 118:1680–1690

    Article  PubMed  CAS  Google Scholar 

  81. Francois Bach J (2003) Regulatory T cells under scrutiny. Nat Rev Immunol 3:189–198 (review)

    Article  PubMed  CAS  Google Scholar 

  82. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061

    Article  PubMed  CAS  Google Scholar 

  83. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329–341

    Article  PubMed  CAS  Google Scholar 

  84. Shevach EM (2002) CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:389–400 (review)

    PubMed  CAS  Google Scholar 

  85. Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, Rubin SC, Kaiser LR, June CH (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

    PubMed  CAS  Google Scholar 

  86. Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC (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

    PubMed  CAS  Google Scholar 

  87. Wang HY, LEE DA, Peng G, Guo Z, Li Y, Kiniwa Y, Shevach EM, Wang RF (2004) Tumor-specific human CD4+ regulatory T cells and their ligands: implication for immunotherapy. Immunity 20:107–118

    Article  PubMed  CAS  Google Scholar 

  88. Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T, Wang DY, Li Y, Wang HY, Wang RF (2005) Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309:1380–1384

    Article  PubMed  CAS  Google Scholar 

  89. 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

    Article  PubMed  CAS  Google Scholar 

  90. Mata-Haro V, Cekic C, Martin M, Chilton PM, Casella CR, Mitchell TC (2007) The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science 316:1628–1632

    Article  PubMed  CAS  Google Scholar 

  91. Yamazaki S, Dudziak D, Heidkamp GF, Fiorese C, Bonito AJ, Inaba K, Nussenzweig MC, Steinman RM (2008) CD8+ CD205+ splenic dendritic cells are specialized to induce Foxp3+ regulatory T cells. J Immunol 181:6923–6933

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  93. Warger T, Osterloh P, Rechtsteiner G, Fassbender M, Heib V, Schmid B, Schmitt E, Schild H, Radsak MP (2006) Synergistic activation of dendritic cells by combined Toll-like receptor ligation induces superior CTL responses in vivo. Blood 108:544–550

    Article  PubMed  CAS  Google Scholar 

  94. Yamazaki S, Bonito AJ, Spisek R, Dhodapkar M, Inaba K, Steinman RM (2007) Dendritic cells are specialized accessory cells along with TGF- for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3 precursors. Blood 110:4293–4302

    Article  PubMed  CAS  Google Scholar 

  95. Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, Shibuya M, Akira S, Aburatani H, Maru Y (2008) The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol 10:1349–1355

    Article  PubMed  CAS  Google Scholar 

  96. Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, Abraham E (2004) Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 279:7370–7377

    Article  PubMed  CAS  Google Scholar 

  97. Shi Y, Evans JE, Rock KL (2003) Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425:516–521

    Article  PubMed  CAS  Google Scholar 

  98. Curtiss LK, Tobias PS (2008) Emerging role of toll-like receptors in atherosclerosis. J Lipid Res 2008 Nov 1 [Epub ahead of print]

  99. Coffelt SB, Scandurro AB (2008) Tumors sound the alarmin(s). Cancer Res 68:6482–6485 (review)

    Article  PubMed  CAS  Google Scholar 

  100. Roux S, Bernat C, Al-Sakere B, Ghiringhelli F, Opolon P, Carpentier AF, Zitvogel L, Mir LM, Robert C (2008) Tumor destruction using electrochemotherapy followed by CpG oligodeoxynucleotide injection induces distant tumor responses. Cancer Immunol Immunother 57:1291–1300 (review)

    Article  PubMed  CAS  Google Scholar 

  101. Ménard C, Martin F, Apetoh L, Bouyer F, Ghiringhelli F (2008) Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity. Cancer Immunol Immunother 57:1579–1587 (review)

    Article  PubMed  Google Scholar 

  102. Seya T, Akazawa T, Uehori J, Matsumoto M, Azuma I, Toyoshima K (2003) Role of toll-like receptors and their adaptors in adjuvant immunotherapy for cancer. Anticancer Res 23:4369–4376 (review)

    PubMed  CAS  Google Scholar 

  103. Nagai Y, Garrett KP, Ohta S, Bahrun U, Kouro T, Akira S, Takatsu K, Kincade PW (2006) Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity 24:801–812

    Article  PubMed  CAS  Google Scholar 

  104. Kleinman ME, Yamada K, Takeda A, Chandrasekaran V, Nozaki M, Baffi JZ, Albuquerque RJ, Yamasaki S, Itaya M, Pan Y, Appukuttan B, Gibbs D, Yang Z, Karikó K, Ambati BK, Wilgus TA, DiPietro LA, Sakurai E, Zhang K, Smith JR, Taylor EW, Ambati J (2008) Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452:591–597

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to our laboratory members for their critical discussions. This work was supported in part by CREST, JST (Japan Science and Technology Corporation), and by Grants-in-Aid from the Ministry of Education, Science, and Culture (Specified Project for Advanced Research) and the Ministry of Health, Labor, and Welfare of Japan, and by the Takeda Science Foundation, Uehara memorial Foundation, Northtec Foundation, Akiyama Foundation, Yakult foundation and Mitsubishi Foundation. Financial supports by the Sapporo Biocluster “Bio-S” the Knowledge Cluster Initiative of the MEXT, and the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases, MEXT are gratefully acknowledged.

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, 060-8638, Japan

    Tsukasa Seya & Misako Matsumoto

Authors
  1. Tsukasa Seya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Misako Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tsukasa Seya.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Seya, T., Matsumoto, M. The extrinsic RNA-sensing pathway for adjuvant immunotherapy of cancer. Cancer Immunol Immunother 58, 1175–1184 (2009). https://doi.org/10.1007/s00262-008-0652-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-008-0652-9

Keywords

Search

Navigation