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Toll-Like Receptors Signaling in the Tumor Microenvironment

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Tumor Microenvironment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1223))

Abstract

The involvement of inflammation in cancer progression is well-established. The immune system can play both tumor-promoting and -suppressive roles, and efforts to harness the immune system to help fight tumor growth are at the forefront of research. Of particular importance is the inflammatory profile at the site of the tumor, with respect to both the leukocyte population numbers, the phenotype of these cells, as well as the contribution of the tumor cells themselves. In this regard, the pro-inflammatory effects of pattern recognition receptor expression and activation in the tumor microenvironment have emerged as a relevant issue both for therapy and to understand tumor development.

Pattern recognition receptors (PRRs) were originally recognized as components of immune cells, particularly innate immune cells, as detectors of pathogens. PRR signaling in immune cells activates them, inducing robust antimicrobial responses. In particular, toll-like receptors (TLRs) constitute a family of membrane-bound PRRs which can recognize pathogen-associated molecular patterns (PAMPs) carried by bacteria, virus, and fungi. In addition, PRRs can recognize products generated by stressed cells or damaged tissues, namely damage-associated molecular patterns or DAMPS. Taking into account the role of the immune system in fighting tumors together with the presence of immune cells in the microenvironment of different types of tumors, strategies to activate immune cells via PRR ligands have been envisioned as an anticancer therapeutic approach.

In the last decades, it has been determined that PRRs are present and functional on nonimmune cells and that their activation in these cells contributes to the inflammation in the tumor microenvironment. Both tumor-promoting and antitumor effects have been observed when tumor cell PRRs are activated. This argues against nonspecific activation of PRR ligands in the tumor microenvironment as a therapeutic approach. Therefore, the use of PRR ligands for anticancer therapy might benefit from strategies that specifically deliver these ligands to immune cells, thus avoiding tumor cells in some settings. This review focuses on these aspects of TLR signaling in the tumor microenvironment.

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References

  1. de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6(1):24–37

    Article  PubMed  CAS  Google Scholar 

  2. Fridman WH et al (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4):298–306

    Article  CAS  PubMed  Google Scholar 

  3. Balkwill FR, Mantovani A (2012) Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol 22(1):33–40

    Article  CAS  PubMed  Google Scholar 

  4. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nelson D, Ganss R (2006) Tumor growth or regression: powered by inflammation. J Leukoc Biol 80(4):685–690

    Article  CAS  PubMed  Google Scholar 

  6. Medzhitov R, Janeway CA Jr (1997) Innate immunity: impact on the adaptive immune response. Curr Opin Immunol 9(1):4–9

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Fearon DT, Locksley RM (1996) The instructive role of innate immunity in the acquired immune response. Science 272(5258):50–53

    Article  CAS  PubMed  Google Scholar 

  9. Dranoff G (2004) Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 4(1):11–22

    Article  CAS  PubMed  Google Scholar 

  10. Finn OJ (2008) Cancer immunology. N Engl J Med 358(25):2704–2715

    Article  CAS  PubMed  Google Scholar 

  11. Hobohm U (2001) Fever and cancer in perspective. Cancer Immunol Immunother 50(8):391–396

    Article  CAS  PubMed  Google Scholar 

  12. Lavoue V et al (2013) Immunity of human epithelial ovarian carcinoma: the paradigm of immune suppression in cancer. J Transl Med 11:147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lin WW, Karin M (2007) A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 117(5):1175–1183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331(6024):1565–1570

    Article  CAS  PubMed  Google Scholar 

  15. Schwartz AL et al (2009) Phenylmethimazole decreases toll-like receptor 3 and noncanonical Wnt5a expression in pancreatic cancer and melanoma together with tumor cell growth and migration. Clin Cancer Res 15(12):4114–4122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ruegg C (2006) Leukocytes, inflammation, and angiogenesis in cancer: fatal attractions. J Leukoc Biol 80(4):682–684

    Article  CAS  PubMed  Google Scholar 

  17. Ronnov-Jessen L et al (1995) The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest 95(2):859–873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kerkar SP, Restifo NP (2012) Cellular constituents of immune escape within the tumor microenvironment. Cancer Res 72(13):3125–3130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ostrand-Rosenberg S et al (2012) Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression. Semin Cancer Biol 22(4):275–281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Egeblad M, Nakasone ES, Werb Z (2010) Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18(6):884–901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Maltby S, Khazaie K, McNagny KM (2009) Mast cells in tumor growth: angiogenesis, tissue remodelling and immune-modulation. Biochim Biophys Acta 1796(1):19–26

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Conejo-Garcia JR et al (2005) Vascular leukocytes contribute to tumor vascularization. Blood 105(2):679–681

    Article  CAS  PubMed  Google Scholar 

  23. Coussens LM, Pollard JW (2011) Leukocytes in mammary development and cancer. Cold Spring Harb Perspect Biol 3(3). https://doi.org/10.1101/cshperspect.a003285

    Google Scholar 

  24. Scarlett UK et al (2012) Ovarian cancer progression is controlled by phenotypic changes in dendritic cells. J Exp Med 209(3):495–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hoption Cann SA et al (2002) Spontaneous regression: a hidden treasure buried in time. Med Hypotheses 58(2):115–119

    Article  CAS  PubMed  Google Scholar 

  26. Zamai L et al (2007) NK cells and cancer. J Immunol 178(7):4011–4016

    Article  CAS  PubMed  Google Scholar 

  27. Marcus A et al (2014) Recognition of tumors by the innate immune system and natural killer cells. Adv Immunol 122:91–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Raulet DH, Guerra N (2009) Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat Rev Immunol 9(8):568–580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Scarlett UK et al (2009) In situ stimulation of CD40 and Toll-like receptor 3 transforms ovarian cancer-infiltrating dendritic cells from immunosuppressive to immunostimulatory cells. Cancer Res 69(18):7329–7337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cubillos-Ruiz JR, Rutkowski M, Conejo-Garcia JR (2010) Blocking ovarian cancer progression by targeting tumor microenvironmental leukocytes. Cell Cycle 9(2):260–268

    Article  CAS  PubMed  Google Scholar 

  31. Benencia F, Muccioli M, Alnaeeli M (2014) Perspectives on reprograming cancer-associated dendritic cells for anti-tumor therapies. Front Oncol 4:72

    Article  PubMed  PubMed Central  Google Scholar 

  32. Adams M et al (2005) The rationale for combined chemo/immunotherapy using a toll-like receptor 3 (TLR3) agonist and tumour-derived exosomes in advanced ovarian cancer. Vaccine 23(17–18):2374–2378

    CAS  PubMed  Google Scholar 

  33. Sica A et al (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42(6):717–727

    Article  CAS  PubMed  Google Scholar 

  34. Dang Y et al (2018) TLR8 ligation induces apoptosis of monocytic myeloid-derived suppressor cells. J Leukoc Biol 103(1):157–164

    Article  CAS  PubMed  Google Scholar 

  35. Yu L, Chen S (2008) Toll-like receptors expressed in tumor cells: targets for therapy. Cancer Immunol Immunother 57(9):1271–1278

    Article  CAS  PubMed  Google Scholar 

  36. Smits EL et al (2008) The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy. Oncologist 13(8):859–875

    Article  CAS  PubMed  Google Scholar 

  37. Smith AL, Robin TP, Ford HL (2012) Molecular pathways: targeting the TGF-beta pathway for cancer therapy. Clin Cancer Res 18(17):4514–4521

    Article  CAS  PubMed  Google Scholar 

  38. Muccioli M et al (2018) Modulation of double-stranded RNA pattern recognition receptor signaling in ovarian cancer cells promotes inflammatory queues. Oncotarget 9(94):36666–36683

    Article  PubMed  PubMed Central  Google Scholar 

  39. Guo Y et al (2012) Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev 38(7):904–910

    Article  CAS  PubMed  Google Scholar 

  40. Venkatesh A et al (2018) Regulation of inflammatory factors by double-stranded RNA receptors in breast cancer cells. Immunobiology 223(6–7):466–476

    Article  CAS  PubMed  Google Scholar 

  41. Goutagny N et al (2012) Targeting pattern recognition receptors in cancer immunotherapy. Target Oncol 7(1):29–54

    Article  PubMed  Google Scholar 

  42. Guiducci C et al (2005) Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res 65(8):3437–3446

    Article  CAS  PubMed  Google Scholar 

  43. Schwartz AL et al (2017) TLR signaling inhibitor, phenylmethimazole, in combination with tamoxifen inhibits human breast cancer cell viability and migration. Oncotarget 8(69):113295–113302

    Article  PubMed  Google Scholar 

  44. Hecht SS (1999) Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 91(14):1194–1210

    Article  CAS  PubMed  Google Scholar 

  45. Auerbach O et al (1961) Changes in bronchial epithelium in relation to cigarette smoking and in relation to lung cancer. N Engl J Med 265:253–267

    Article  CAS  PubMed  Google Scholar 

  46. Seitz HK, Simanowski UA (1988) Alcohol and carcinogenesis. Annu Rev Nutr 8:99–119

    Article  CAS  PubMed  Google Scholar 

  47. Seitz HK, Stickel F (2007) Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 7(8):599–612

    Article  CAS  PubMed  Google Scholar 

  48. Conejo-Garcia JR et al (2004) Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-a. Nat Med 10(9):950–958

    Article  CAS  PubMed  Google Scholar 

  49. Huarte E et al (2008) Depletion of dendritic cells delays ovarian cancer progression by boosting antitumor immunity. Cancer Res 68(18):7684–7691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Curiel TJ et al (2004) Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer. Cancer Res 64(16):5535–5538

    Article  CAS  PubMed  Google Scholar 

  51. Riboldi E et al (2005) Cutting edge: proangiogenic properties of alternatively activated dendritic cells. J Immunol 175(5):2788–2792

    Article  CAS  PubMed  Google Scholar 

  52. Conrad C et al (2012) Plasmacytoid dendritic cells promote immunosuppression in ovarian cancer via ICOS costimulation of Foxp3(+) T-regulatory cells. Cancer Res 72(20):5240–5249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mantovani A et al (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555

    Article  CAS  PubMed  Google Scholar 

  54. Hagemann T et al (2006) Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J Immunol 176(8):5023–5032

    Article  CAS  PubMed  Google Scholar 

  55. Heusinkveld M, van der Burg SH (2011) Identification and manipulation of tumor associated macrophages in human cancers. J Transl Med 9:216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wang X et al (2013) Interaction of monocytes/macrophages with ovarian cancer cells promotes angiogenesis in vitro. Cancer Sci 104(4):516–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Goyne HE et al (2014) Ovarian tumor ascites CD14+ cells suppress dendritic cell-activated CD4+ T-cell responses through IL-10 secretion and indoleamine 2,3-dioxygenase. J Immunother 37(3):163–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hernandez L et al (2010) Activation of NF-kappaB signaling by inhibitor of NF-kappaB kinase beta increases aggressiveness of ovarian cancer. Cancer Res 70(10):4005–4014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Karin M et al (2002) NF-kappa B in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2(4):301–310

    Article  CAS  PubMed  Google Scholar 

  60. Wu Y, Zhou BP (2010) TNF-alpha/NF-kappa B/Snail pathway in cancer cell migration and invasion. Br J Cancer 102(4):639–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Annunziata CM et al (2010) Nuclear factor kappa B transcription factors are coexpressed and convey a poor outcome in ovarian cancer. Cancer 116(13):3276–3284

    Article  CAS  PubMed  Google Scholar 

  62. Killeen SD et al (2006) Exploitation of the toll-like receptor system in cancer: a doubled-edged sword? Br J Cancer 95(3):247–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chen KQ et al (2007) Toll-like receptors in inflammation, infection and cancer. Int Immunopharmacol 7(10):1271–1285

    Article  CAS  PubMed  Google Scholar 

  64. Chuang HC et al (2012) Toll-like receptor 3-mediated tumor invasion in head and neck cancer. Oral Oncol 48(3):226–232

    Article  CAS  PubMed  Google Scholar 

  65. McCall KD et al (2007) High basal levels of functional toll-like receptor 3 (TLR3) and noncanonical Wnt5a are expressed in papillary thyroid cancer and are coordinately decreased by phenylmethimazole together with cell proliferation and migration. Endocrinology 148(9):4226–4237

    Article  CAS  PubMed  Google Scholar 

  66. Noori MS et al (2017) Phenylmethimazole and a thiazole derivative of phenylmethimazole inhibit IL-6 expression by triple negative breast cancer cells. Eur J Pharmacol 803:130–137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bellora F et al (2014) TLR activation of tumor-associated macrophages from ovarian cancer patients triggers cytolytic activity of NK cells. Eur J Immunol 44(6):1814–1822

    Article  CAS  PubMed  Google Scholar 

  68. Chefetz I et al (2013) TLR2 enhances ovarian cancer stem cell self-renewal and promotes tumor repair and recurrence. Cell Cycle 12(3):511–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Conforti R et al (2010) Opposing effects of toll-like receptor (TLR3) signaling in tumors can be therapeutically uncoupled to optimize the anticancer efficacy of TLR3 ligands. Cancer Res 70(2):490–500

    Article  CAS  PubMed  Google Scholar 

  70. He WG et al (2007) TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. Mol Immunol 44(11):2850–2859

    Article  CAS  PubMed  Google Scholar 

  71. Kelly MG et al (2006) TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res 66(7):3859–3868

    Article  CAS  PubMed  Google Scholar 

  72. Matijevic T, Pavelic J (2011) The dual role of TLR3 in metastatic cell line. Clin Exp Metastasis 28(7):701–712

    Article  CAS  PubMed  Google Scholar 

  73. Salaun B et al (2006) TLR3 can directly trigger apoptosis in human cancer cells. J Immunol 176(8):4894–4901

    Article  CAS  PubMed  Google Scholar 

  74. Woods DC et al (2011) TLR4 activates NF-kappa B in human ovarian granulosa tumor cells. Biochem Biophys Res Commun 409(4):675–680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gordon S (2002) Pattern recognition receptors: doubling up for the innate immune response. Cell 111(7):927–930

    Article  CAS  PubMed  Google Scholar 

  76. Meylan E, Tschopp J, Karin M (2006) Intracellular pattern recognition receptors in the host response. Nature 442(7098):39–44

    Article  CAS  PubMed  Google Scholar 

  77. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140(6):805–820

    Article  CAS  PubMed  Google Scholar 

  78. Matsukura S et al (2007) Role of RIG-I, MDA-5, and PKR on the expression of inflammatory chemokines induced by synthetic dsRNA in airway epithelial cells. Int Arch Allergy Immunol 143:80–83

    Article  CAS  PubMed  Google Scholar 

  79. Chen R et al (2007) Inflammation, cancer and chemoresistance: taking advantage of the toll-like receptor signaling pathway. Am J Reprod Immunol 57(2):93–107

    Article  CAS  PubMed  Google Scholar 

  80. Zhou MF et al (2009) Toll-like receptor expression in normal ovary and ovarian tumors. Cancer Immunol Immunother 58(9):1375–1385

    Article  CAS  PubMed  Google Scholar 

  81. O’Neill LA (2003) Therapeutic targeting of toll-like receptors for inflammatory and infectious diseases. Curr Opin Pharmacol 3(4):396–403

    Article  PubMed  CAS  Google Scholar 

  82. Matijevic T, Marjanovic M, Pavelic J (2009) Functionally active Toll-like receptor 3 on human primary and metastatic cancer cells. Scand J Immunol 70(1):18–24

    Article  CAS  PubMed  Google Scholar 

  83. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11(5):373–384

    Article  CAS  PubMed  Google Scholar 

  84. Roh JS, Sohn DH (2018) Damage-associated molecular patterns in inflammatory diseases. Immune Netw 18(4):e27

    Article  PubMed  PubMed Central  Google Scholar 

  85. Muccioli M et al (2012) Toll-like receptors as novel therapeutic targets for ovarian cancer. ISRN Oncol 2012:642141

    PubMed  PubMed Central  Google Scholar 

  86. Huang B et al (2008) TLR signaling by tumor and immune cells: a double-edged sword. Oncogene 27(2):218–224

    Article  CAS  PubMed  Google Scholar 

  87. Muccioli M, Benencia F (2014) Toll-like receptors in ovarian cancer as targets for immunotherapies. Front Immunol 5:341

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Chen R et al (2008) Cancers take their Toll–the function and regulation of Toll-like receptors in cancer cells. Oncogene 27(2):225–233

    Article  CAS  PubMed  Google Scholar 

  89. Seya T, Matsumoto M (2009) The extrinsic RNA-sensing pathway for adjuvant immunotherapy of cancer. Cancer Immunol Immunother 58(8):1175–1184

    Article  CAS  PubMed  Google Scholar 

  90. Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2(8):675–680

    Article  CAS  PubMed  Google Scholar 

  91. Takeda K, Akira S (2004) TLR signaling pathways. Semin Immunol 16(1):3–9

    Article  CAS  PubMed  Google Scholar 

  92. Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376

    Article  CAS  PubMed  Google Scholar 

  93. Harii N et al (2005) Thyrocytes express a functional toll-like receptor 3: overexpression can be induced by viral infection and reversed by phenylmethimazole and is associated with Hashimoto’s autoimmune thyroiditis. Mol Endocrinol 19(5):1231–1250

    Article  CAS  PubMed  Google Scholar 

  94. Wong FS et al (2008) The role of Toll-like receptors 3 and 9 in the development of autoimmune diabetes in NOD mice. Ann N Y Acad Sci 1150:146–148

    Article  PubMed  Google Scholar 

  95. McCall KD et al (2013) Phenylmethimazole suppresses dsRNA-induced cytotoxicity and inflammatory cytokines in murine pancreatic Beta cells and blocks viral acceleration of type 1 diabetes in NOD mice. Molecules 18(4):3841–3858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bsibsi M et al (2002) Broad expression of toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 61(11):1013–1021

    Article  CAS  PubMed  Google Scholar 

  97. Van DN et al (2012) Innate immune agonist, dsRNA, induces apoptosis in ovarian cancer cells and enhances the potency of cytotoxic chemotherapeutics. FASEB J 26(8):3188–3198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13(5):816–825

    Article  CAS  PubMed  Google Scholar 

  99. Krown SE et al (1985) Phase-I trials of Poly(I,C) complexes in advanced cancer. J Biol Response Mod 4(6):640–649

    CAS  PubMed  Google Scholar 

  100. Robinson RA et al (1976) Phase 1-2 trial of multiple-dose polyriboinosinic-polyribocytidylic acid in patients with Leukemia or solid tumors. J Natl Cancer Inst 57(3):599–602

    Article  CAS  PubMed  Google Scholar 

  101. Geller MA et al (2010) Toll-like receptor-7 agonist administered subcutaneously in a prolonged dosing schedule in heavily pretreated recurrent breast, ovarian, and cervix cancers. Cancer Immunol Immunother 59(12):1877–1884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ayari C et al (2016) Poly(I:C) potentiates bacillus Calmette-Guerin immunotherapy for bladder cancer. Cancer Immunol Immunother 65(2):223–234

    Article  CAS  PubMed  Google Scholar 

  103. Yi DH et al (2018) 3-day monocyte-derived dendritic cells stimulated with a combination of OK432, TLR7/8 ligand, and prostaglandin E2 are a promising alternative for cancer immunotherapy. Cancer Immunol Immunother 67(10):1611–1620

    Article  CAS  PubMed  Google Scholar 

  104. Pearson FE et al (2018) Activation of human CD141(+) and CD1c(+) dendritic cells in vivo with combined TLR3 and TLR7/8 ligation. Immunol Cell Biol 96(4):390–400

    Article  CAS  PubMed  Google Scholar 

  105. Wu CC et al (2016) A toll-like receptor 2 agonist-fused antigen enhanced antitumor immunity by increasing antigen presentation and the CD8 memory T cells population. Oncotarget 7(21):30804–30819

    Article  PubMed  PubMed Central  Google Scholar 

  106. Nocera DA et al (2016) In vivo visualizing the IFN-beta response required for tumor growth control in a therapeutic model of Polyadenylic-Polyuridylic acid administration. J Immunol 196(6):2860–2869

    Article  CAS  PubMed  Google Scholar 

  107. Wang S et al (2016) Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8+ T cells. Proc Natl Acad Sci U S A 113(46):E7240–E7249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wang D et al (2018) Modulation of the tumor microenvironment by intratumoral administration of IMO-2125, a novel TLR9 agonist, for cancer immunotherapy. Int J Oncol 53(3):1193–1203

    CAS  PubMed  Google Scholar 

  109. Liu MG et al (2019) Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47-mediated ‘don’t-eat-me’ signal. Nat Immunol 20(3):265–275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Rodell CB et al (2018) TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat Biomed Eng 2(8):578–588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Klauber TCB et al (2017) Delivery of TLR7 agonist to monocytes and dendritic cells by DCIR targeted liposomes induces robust production of anti-cancer cytokines. Acta Biomater 53:367–377

    Article  CAS  PubMed  Google Scholar 

  112. Dietsch GN et al (2016) Coordinated activation of Toll-like Receptor8 (TLR8) and NLRP3 by the TLR8 agonist, VTX-2337, ignites Tumoricidal natural killer cell activity. PLoS One 11(2):e0148764

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Yang H et al (2016) The toll-like receptor 5 agonist entolimod suppresses hepatic metastases in a murine model of ocular melanoma via an NK cell-dependent mechanism. Oncotarget 7(3):2936–2950

    PubMed  Google Scholar 

  114. Brackett CM et al (2016) Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8(+) T-cell axis. Proc Natl Acad Sci U S A 113(7):E874–E883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Cho JH et al (2017) The TLR7 agonist imiquimod induces anti-cancer effects via autophagic cell death and enhances anti-tumoral and systemic immunity during radiotherapy for melanoma. Oncotarget 8(15):24932–24948

    Article  PubMed  PubMed Central  Google Scholar 

  116. Dovedi SJ et al (2016) Intravenous administration of the selective toll-like receptor 7 agonist DSR-29133 leads to anti-tumor efficacy in murine solid tumor models which can be potentiated by combination with fractionated radiotherapy. Oncotarget 7(13):17035–17046

    Article  PubMed  PubMed Central  Google Scholar 

  117. Yoshida S et al (2018) Toll-like receptor 3 signal augments radiation-induced tumor growth retardation in a murine model. Cancer Sci 109(4):956–965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bauer AK et al (2017) Toll-like receptor expression in human non-small cell lung carcinoma: potential prognostic indicators of disease. Oncotarget 8(54):91860–91875

    Article  PubMed  PubMed Central  Google Scholar 

  119. Lanki MA et al (2018) Toll-like receptor 2 and toll-like receptor 4 predict favorable prognosis in local pancreatic cancer. Tumour Biol 40(9):1010428318801188

    Article  PubMed  CAS  Google Scholar 

  120. Kusuhara Y et al (2019) Low expression of Toll-like receptor 4 is associated with poor prognosis in bladder cancer. Anticancer Res 39(2):703–711

    Article  PubMed  Google Scholar 

  121. Jiang Q, Wei HM, Tian ZG (2008) Poly I: C enhances cycloheximide-induced apoptosis of tumor cells through TLR3 pathway. BMC Cancer 8:12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Peng GY et al (2005) Toll-like, receptor 8-mediated reversal of CD4(+) regulatory T cell function. Science 309(5739):1380–1384

    Article  CAS  PubMed  Google Scholar 

  123. Lu H et al (2012) VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC. Clin Cancer Res 18(2):499–509

    Article  CAS  PubMed  Google Scholar 

  124. Kohtz PD et al (2019) Toll-like Receptor-4 is a mediator of proliferation in esophageal adenocarcinoma. Ann Thorac Surg 107(1):233–241

    Article  PubMed  Google Scholar 

  125. Huhta H et al (2016) Toll-like receptors 1, 2, 4 and 6 in esophageal epithelium, Barrett’s esophagus, dysplasia and adenocarcinoma. Oncotarget 7(17):23658–23667

    Article  PubMed  PubMed Central  Google Scholar 

  126. Sun YL et al (2016) Toll-like receptor 4 promotes angiogenesis in pancreatic cancer via PI3K/AKT signaling. Exp Cell Res 347(2):274–282

    Article  CAS  PubMed  Google Scholar 

  127. Huy H et al (2018) TLR4/NF-kappa B axis induces fludarabine resistance by suppressing TXNIP expression in acute myeloid leukemia cells. Biochem Biophys Res Commun 506(1):33–40

    Article  CAS  PubMed  Google Scholar 

  128. Sootichote R et al (2018) Compound a attenuates toll-like receptor 4-mediated paclitaxel resistance in breast cancer and melanoma through suppression of IL-8. BMC Cancer 18(1):231

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Messaritakis I et al (2018) Evaluation of the detection of Toll-like receptors (TLRs) in cancer development and progression in patients with colorectal cancer. PLoS One 13(6):e0197327

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Block MS et al (2018) MyD88 and TLR4 expression in epithelial ovarian cancer. Mayo Clin Proc 93(3):307–320

    Article  CAS  PubMed  Google Scholar 

  131. Wu K et al (2018) TLR4/MyD88 signaling determines the metastatic potential of breast cancer cells. Mol Med Rep 18(3):3411–3420

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Jiang N et al (2017) Toll-like receptor 4 promotes proliferation and apoptosis resistance in human papillomavirus-related cervical cancer cells through the Toll-like receptor 4/nuclear factor-kappaB pathway. Tumour Biol 39(6):1010428317710586

    PubMed  Google Scholar 

  133. Palani CD et al (2018) Toll-like receptor 2 induces adenosine receptor A2a and promotes human squamous carcinoma cell growth via extracellular signal regulated kinases (1/2). Oncotarget 9(6):6814–6829

    Article  PubMed  Google Scholar 

  134. Mastorci K et al (2016) Toll-like receptor 1/2 and 5 ligands enhance the expression of Cyclin D1 and D3 and induce proliferation in mantle cell lymphoma. PLoS One 11(4):e0153823

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Ikehata N et al (2018) Toll-like receptor 2 activation implicated in oral squamous cell carcinoma development. Biochem Biophys Res Commun 495(3):2227–2234

    Article  CAS  PubMed  Google Scholar 

  136. Liu B et al (2016) TLR2 promotes human intrahepatic cholangiocarcinoma cell migration and invasion by modulating NF-kappaB pathway-mediated inflammatory responses. FEBS J 283(20):3839–3850

    Article  CAS  PubMed  Google Scholar 

  137. Li CL et al (2019) TLR2 promotes development and progression of human glioma via enhancing autophagy. Gene 700:52–59

    Article  CAS  PubMed  Google Scholar 

  138. West AC et al (2017) Identification of a TLR2-regulated gene signature associated with tumor cell growth in gastric cancer. Oncogene 36(36):5134–5144

    Article  CAS  PubMed  Google Scholar 

  139. Maslinska D et al (2015) Toll-like receptor 2 (TLR2) is a marker of angiogenesis in the necrotic area of human medulloblastoma. Folia Neuropathol 53(4):347–354

    Article  PubMed  Google Scholar 

  140. Gowing SD et al (2017) Gram-positive pneumonia augments non-small cell lung cancer metastasis via host toll-like receptor 2 activation. Int J Cancer 141(3):561–571

    Article  CAS  PubMed  Google Scholar 

  141. Bugge M et al (2017) Surface Toll-like receptor 3 expression in metastatic intestinal epithelial cells induces inflammatory cytokine production and promotes invasiveness. J Biol Chem 292(37):15408–15425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Veyrat M et al (2016) Stimulation of the toll-like receptor 3 promotes metabolic reprogramming in head and neck carcinoma cells. Oncotarget 7(50):82580–82593

    Article  PubMed  PubMed Central  Google Scholar 

  143. Boes M, Meyer-Wentrup F (2015) TLR3 triggering regulates PD-L1 (CD274) expression in human neuroblastoma cells. Cancer Lett 361(1):49–56

    Article  CAS  PubMed  Google Scholar 

  144. Maitra R et al (2017) Toll like receptor 3 as an immunotherapeutic target for KRAS mutated colorectal cancer. Oncotarget 8(21):35138–35153

    Article  PubMed  PubMed Central  Google Scholar 

  145. Jing YB et al (2015) Up-regulation of Toll-like receptor 9 in osteosarcoma. Anticancer Res 35(11):5839–5843

    CAS  PubMed  Google Scholar 

  146. Won H et al (2017) TLR9 expression and secretion of LIF by prostate cancer cells stimulates accumulation and activity of polymorphonuclear MDSCs. J Leukoc Biol 102(2):423–436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Sandholm J et al (2016) Toll-like receptor 9 expression is associated with breast cancer sensitivity to the growth inhibitory effects of bisphosphonates in vitro and in vivo. Oncotarget 7(52):87373–87389

    Article  PubMed  PubMed Central  Google Scholar 

  148. Honda K, Taniguchi T (2006) IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol 6(9):644–658

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by the NIH under Grant R15 CA137499-01 (FB), a startup fund from OU (FB), a Research and Scholarly Awards Committee grant (RP1206) from the Heritage College of Osteopathic Medicine, OU; and Ohio University-Baker Funds Award (FN1006078). Figures were created using the Library of Science and Medical Illustrations free resource (https://www.somersault1824.com/science-illustrations/)

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Authors and Affiliations

  1. Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA

    Kelly D. McCall

  2. Molecular and Cellular Biology Program, Ohio University, Athens, OH, USA

    Kelly D. McCall & Fabian Benencia

  3. Diabetes Institute, Ohio University, Athens, OH, USA

    Kelly D. McCall & Fabian Benencia

  4. Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA

    Maria Muccioli & Fabian Benencia

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  1. Kelly D. McCall
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  2. Maria Muccioli
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  3. Fabian Benencia
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Correspondence to Fabian Benencia .

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  1. Columbia University Medical Center, Department of Radiology, New York, NY, USA, Federal University of Minas Gerais, Department of Pathology, Belo Horizonte, Minas Gerais, Brazil

    Alexander Birbrair

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McCall, K.D., Muccioli, M., Benencia, F. (2020). Toll-Like Receptors Signaling in the Tumor Microenvironment. In: Birbrair, A. (eds) Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 1223. Springer, Cham. https://doi.org/10.1007/978-3-030-35582-1_5

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