Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Targeted Oncology
Published in: Targeted Oncology 5/2018

01-10-2018 | Review Article

Targeting Toll-Like Receptors for Cancer Therapy

Authors: Marc J. Braunstein, John Kucharczyk, Sylvia Adams

Published in: Targeted Oncology | Issue 5/2018

Login to get access

Abstract

The immune system encompasses a broad array of defense mechanisms against foreign threats, including invading pathogens and transformed neoplastic cells. Toll-like receptors (TLRs) are critically involved in innate immunity, serving as pattern recognition receptors whose stimulation leads to additional innate and adaptive immune responses. Malignant cells exploit the natural immunomodulatory functions of TLRs, expressed mainly by infiltrating immune cells but also aberrantly by tumor cells, to foster their survival, invasion, and evasion of anti-tumor immune responses. An extensive body of research has demonstrated context-specific roles for TLR activation in different malignancies, promoting disease progression in certain instances while limiting cancer growth in others. Despite these conflicting roles, TLR agonists have established therapeutic benefits as anti-cancer agents that activate immune cells in the tumor microenvironment and facilitate the expression of cytokines that allow for infiltration of anti-tumor lymphocytes and the suppression of oncogenic signaling pathways. This review focuses on the clinical application of TLR agonists for cancer treatment. We also highlight agents that are undergoing development in clinical trials, including investigations of TLR agonists in combination with other immunotherapies.
Appendix
Available only for authorised users
Literature
1.
Couzin-Frankel J. Breakthrough of the year 2013. Cancer Immunotherapy. Science. 2013;342(6165):1432–3.PubMedCrossRef
2.
Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011;331(6024):1565–70.PubMedCrossRef
3.
Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783–801.PubMedCrossRef
4.
Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996;86(6):973–83.CrossRefPubMed
5.
Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388(6640):394–7.PubMedCrossRef
6.
O'Neill LA, Golenbock D, Bowie AG. The history of Toll-like receptors - redefining innate immunity. Nat Rev Immunol. 2013;13(6):453–60.PubMedCrossRef
7.
Tartey S,Takeuchi O. Toll-like receptors: role in inflammation and cancer, cancer and inflammation mechanisms: chemical, biological, and clinical aspects, First Edition. Hoboken: John Wiley & Sons, Inc; 2014. Chapter 7.CrossRef
8.
Barton GM, Kagan JC. A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol. 2009;9(8):535–42.PubMedPubMedCentralCrossRef
9.
Goutagny N, Estornes Y, Hasan U, Lebecque S, Caux C. Targeting pattern recognition receptors in cancer immunotherapy. Target Oncol. 2012;7(1):29–54.PubMedCrossRef
10.
Mastorci K, Muraro E, Pasini E, Furlan C, Sigalotti L, Cinco M, et al. 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. 2016;11(4):e0153823.PubMedPubMedCentralCrossRef
11.
Abdi J, et al. Toll-like receptor (TLR)-1/2 triggering of multiple myeloma cells modulates their adhesion to bone marrow stromal cells and enhances bortezomib-induced apoptosis. PLoS One. 2014;9(5):e96608.PubMedPubMedCentralCrossRef
12.
Fonte E, et al. Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling, activation and proliferation. Haematologica. 2015;100(11):1460–8.PubMedPubMedCentralCrossRef
13.
Oldford SA, et al. A critical role for mast cells and mast cell-derived IL-6 in TLR2-mediated inhibition of tumor growth. J Immunol. 2010;185(11):7067–76.PubMedCrossRef
14.
Chuang HC, et al. Toll-like receptor 3-mediated tumor invasion in head and neck cancer. Oral Oncol. 2012;48(3):226–32.PubMedCrossRef
15.
Gambara G, et al. TLR3 engagement induces IRF-3-dependent apoptosis in androgen-sensitive prostate cancer cells and inhibits tumour growth in vivo. J Cell Mol Med. 2015;19(2):327–39.PubMedCrossRef
16.
Wang EL, Qian ZR, Nakasono M, Tanahashi T, Yoshimoto K, Bando Y, et al. High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer. Br J Cancer. 2010;102(5):908–15.PubMedPubMedCentralCrossRef
17.
Fang H, Ang B, Xu X, Huang X, Wu Y, Sun Y, et al. TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells. Cell Mol Immunol. 2014;11(2):150–9.CrossRefPubMed
18.
Omar AA, et al. Toll-like receptors -4 and -5 in oral and cutaneous squamous cell carcinomas. J Oral Pathol Med. 2015;44(4):258–65.PubMedCrossRef
19.
Cai Z, et al. Activation of Toll-like receptor 5 on breast cancer cells by flagellin suppresses cell proliferation and tumor growth. Cancer Res. 2011;71(7):2466–75.PubMedPubMedCentralCrossRef
20.
Jego G, et al. Pathogen-associated molecular patterns are growth and survival factors for human myeloma cells through Toll-like receptors. Leukemia. 2006;20(6):1130–7.PubMedCrossRef
21.
Wang F, et al. Activation of Toll-like receptor 7 regulates the expression of IFN-lambda1, p53, PTEN, VEGF, TIMP-1 and MMP-9 in pancreatic cancer cells. Mol Med Rep. 2016;13(2):1807–12.PubMedCrossRef
22.
Cherfils-Vicini J, Platonova S, Gillard M, Laurans L, Validire P, Caliandro R, et al. Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. J Clin Invest. 2010;120(4):1285–97.PubMedPubMedCentralCrossRef
23.
24.
Tanaka J, Sugimoto K, Shiraki K, Tameda M, Kusagawa S, Nojiri K, et al. Functional cell surface expression of Toll-like receptor 9 promotes cell proliferation and survival in human hepatocellular carcinomas. Int J Oncol. 2010;37(4):805–14.PubMedCrossRef
25.
Brignole C, Marimpietri D, Di Paolo D, Perri P, Morandi F, Pastorino F, et al. Therapeutic targeting of TLR9 inhibits cell growth and induces apoptosis in neuroblastoma. Cancer Res. 2010;70(23):9816–26.PubMedCrossRef
26.
Yu L, Wang L, Chen S. Dual character of Toll-like receptor signaling: pro-tumorigenic effects and anti-tumor functions. Biochim Biophys Acta. 2013;1835(2):144–54.PubMed
27.
Basith S, Manavalan B, Yoo TH, Kim SG, Choi S. Roles of Toll-like receptors in cancer: a double-edged sword for defense and offense. Arch Pharm Res. 2012;35(8):1297–316.PubMedCrossRef
28.
Dajon M, Iribarren K, Cremer I. Toll-like receptor stimulation in cancer: a pro- and anti-tumor double-edged sword. Immunobiology. 2017;222(1):89–100.PubMedCrossRef
29.
Sasai M, Yamamoto M. Pathogen recognition receptors: ligands and signaling pathways by Toll-like receptors. Int Rev Immunol. 2013;32(2):116–33.PubMedCrossRef
30.
Jimenez-Dalmaroni MJ, Gerswhin ME, Adamopoulos IE. The critical role of Toll-like receptors--from microbial recognition to autoimmunity: a comprehensive review. Autoimmun Rev. 2016;15(1):1–8.PubMedCrossRef
31.
Cammarota R, Bertolini V, Pennesi G, Bucci EO, Gottardi O, Garlanda C, et al. The tumor microenvironment of colorectal cancer: stromal TLR-4 expression as a potential prognostic marker. J Transl Med. 2010;8:112.PubMedPubMedCentralCrossRef
32.
Hennessy EJ, Parker AE, O'Neill LA. Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov. 2010;9(4):293–307.PubMedCrossRef
33.
Tartey S, Takeuchi O. Pathogen recognition and Toll-like receptor targeted therapeutics in innate immune cells. Int Rev Immunol. 2017:1–17.
34.
35.
Broad A, Kirby JA, Jones DE. Toll-like receptor interactions: tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon-beta production. Immunology. 2007;120(1):103–11.PubMedPubMedCentralCrossRef
36.
Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature. 2001;410(6832):1099–103.PubMedCrossRef
37.
Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, et al. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science. 2003;301(5633):640–3.PubMedCrossRef
38.
Li TT, Ogino S, Qian ZR. Toll-like receptor signaling in colorectal cancer: carcinogenesis to cancer therapy. World J Gastroenterol. 2014;20(47):17699–708.PubMedPubMedCentralCrossRef
39.
Gasse P, Mary C, Guenon I, Noulin N, Charron S, Schnyder-Candrian S, et al. IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J Clin Invest. 2007;117(12):3786–99.PubMedPubMedCentral
40.
Picard C, Casanova JL, Puel A. Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IkappaBalpha deficiency. Clin Microbiol Rev. 2011;24(3):490–7.PubMedPubMedCentralCrossRef
41.
Pradere JP, Dapito DH, Schwabe RF. The yin and Yang of Toll-like receptors in cancer. Oncogene. 2014;33(27):3485–95.PubMedCrossRef
42.
Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med. 2005;11(11):1173–9.PubMedCrossRef
43.
Cannova J, Breslin SJP, Zhang J. Toll-like receptor signaling in hematopoietic homeostasis and the pathogenesis of hematologic diseases. Front Med. 2015;9(3):288–303.PubMedCrossRef
44.
45.
Matijevic T, Pavelic J. Toll-like receptors: cost or benefit for cancer? Curr Pharm Des. 2010;16(9):1081–90.PubMedCrossRef
46.
47.
LaRue H, Ayari C, Bergeron A, Fradet Y. Toll-like receptors in urothelial cells--targets for cancer immunotherapy. Nat Rev Urol. 2013;10(9):537–45.PubMedCrossRef
48.
Wang Z, Yan J, Lin H, Hua F, Wang X, Liu H, et al. Toll-like receptor 4 activity protects against hepatocellular tumorigenesis and progression by regulating expression of DNA repair protein Ku70 in mice. Hepatology. 2013;57(5):1869–81.PubMedCrossRef
49.
Liu WT, Jing YY, Yu GF, Han ZP, Yu DD, Fan QM, et al. Toll like receptor 4 facilitates invasion and migration as a cancer stem cell marker in hepatocellular carcinoma. Cancer Lett. 2015;358(2):136–43.PubMedCrossRef
50.
Bohnhorst J, Rasmussen T, Moen SH, Flottum M, Knudsen L, Borset M, et al. Toll-like receptors mediate proliferation and survival of multiple myeloma cells. Leukemia. 2006;20(6):1138–44.PubMedCrossRef
51.
O'Leary DP, Bhatt L, Woolley JF, Gough DR, Wang JH, Cotter TG, et al. TLR-4 signalling accelerates colon cancer cell adhesion via NF-kappaB mediated transcriptional up-regulation of Nox-1. PLoS One. 2012;7(10):e44176.PubMedPubMedCentralCrossRef
52.
Ridnour LA, Cheng RY, Switzer CH, Heinecke JL, Ambs S, Glynn S, et al. Molecular pathways: Toll-like receptors in the tumor microenvironment--poor prognosis or new therapeutic opportunity. Clin Cancer Res. 2013;19(6):1340–6.PubMedCrossRef
53.
Huang B, Zhao J, Li H, He KL, Chen Y, Chen SH, et al. Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res. 2005;65(12):5009–14.PubMedCrossRef
54.
Yang H, Wang B, Wang T, Xu L, He C, Wen H, et al. Toll-like receptor 4 prompts human breast cancer cells invasiveness via lipopolysaccharide stimulation and is overexpressed in patients with lymph node metastasis. PLoS One. 2014;9(10):e109980.PubMedPubMedCentralCrossRef
55.
Huang Y, Cai B, Xu M, Qiu Z, Tao Y, Zhang Y, et al. Gene silencing of Toll-like receptor 2 inhibits proliferation of human liver cancer cells and secretion of inflammatory cytokines. PLoS One. 2012;7(7):e38890.PubMedPubMedCentralCrossRef
56.
Yang H, Zhou H, Feng P, Zhou X, Wen H, Xie X, et al. Reduced expression of Toll-like receptor 4 inhibits human breast cancer cells proliferation and inflammatory cytokines secretion. J Exp Clin Cancer Res. 2010;29:92.PubMedPubMedCentralCrossRef
57.
Kim S, Takahashi H, Lin WW, Descargues P, Grivennikov S, Kim Y, et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature. 2009;457(7225):102–6.PubMedPubMedCentralCrossRef
58.
Stevens VL, Hsing AW, Talbot JT, Zheng SL, Sun J, Chen J, et al. Genetic variation in the Toll-like receptor gene cluster (TLR10-TLR1-TLR6) and prostate cancer risk. Int J Cancer. 2008;123(11):2644–50.PubMedCrossRef
59.
Castano-Rodriguez N, Kaakoush NO, Goh KL, Fock KM, Mitchell HM. The role of TLR2, TLR4 and CD14 genetic polymorphisms in gastric carcinogenesis: a case-control study and meta-analysis. PLoS One. 2013;8(4):e60327.PubMedPubMedCentralCrossRef
60.
61.
Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539–45.CrossRefPubMed
62.
Ben-Neriah Y, Karin M. Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat Immunol. 2011;12(8):715–23.PubMedCrossRef
63.
Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441(7092):431–6.CrossRefPubMed
64.
Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431(7007):461–6.CrossRefPubMed
65.
Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4(1):71–8.CrossRefPubMed
66.
Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008;8(8):618–31.PubMedCrossRef
67.
Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185.PubMedPubMedCentralCrossRef
68.
Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 2013;14(6):e218–28.PubMedCrossRef
69.
Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ. HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol. 2010;28:367–88.CrossRefPubMed
70.
Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13(9):1050–9.PubMedCrossRef
71.
Waki K, Yamada A. Blockade of high mobility group box 1 augments antitumor T-cell response induced by peptide vaccination as a co-adjuvant. Cancer Sci. 2016;107(12):1721–9.PubMedPubMedCentralCrossRef
72.
Abreu MT. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol. 2010;10(2):131–44.PubMedCrossRef
73.
Han S, Xu W, Wang Z, Qi X, Wang Y, Ni Y, et al. Crosstalk between the HIF-1 and Toll-like receptor/nuclear factor-kappaB pathways in the oral squamous cell carcinoma microenvironment. Oncotarget. 2016;7(25):37773–89.PubMedPubMedCentralCrossRef
74.
Wang RF, Peng G, Wang HY. Regulatory T cells and Toll-like receptors in tumor immunity. Semin Immunol. 2006;18(2):136–42.PubMedCrossRef
75.
76.
Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.CrossRefPubMed
77.
Palani CD, Ramanathapuram L, Lam-Ubol A, Kurago ZB. Toll-like receptor 2 induces adenosine receptor A2a and promotes human squamous carcinoma cell growth via extracellular signal regulated kinases (1/2). Oncotarget. 2018;9(6):6814–29.PubMedCrossRef
78.
79.
Szczepanski MJ, Czystowska M, Szajnik M, Harasymczuk M, Boyiadzis M, Kruk-Zagajewska A, et al. Triggering of Toll-like receptor 4 expressed on human head and neck squamous cell carcinoma promotes tumor development and protects the tumor from immune attack. Cancer Res. 2009;69(7):3105–13.PubMedPubMedCentralCrossRef
80.
Fukata M, Chen A, Vamadevan AS, Cohen J, Breglio K, Krishnareddy S, et al. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology. 2007;133(6):1869–81.PubMedCrossRef
81.
Chen CL, Tsukamoto H, Liu JC, Kashiwabara C, Feldman D, Sher L, et al. Reciprocal regulation by TLR4 and TGF-beta in tumor-initiating stem-like cells. J Clin Invest. 2013;123(7):2832–49.PubMedPubMedCentralCrossRef
82.
Uthaya Kumar DB, Chen CL, Liu JC, Feldman DE, Sher LS, French S, et al. TLR4 signaling via NANOG cooperates with STAT3 to activate Twist1 and promote formation of tumor-initiating stem-like cells in livers of mice. Gastroenterology. 2016;150(3):707–19.PubMedCrossRef
83.
Alvarado AG, Thiagarajan PS, Mulkearns-Hubert EE, Silver DJ, Hale JS, Alban TJ, et al. Glioblastoma cancer stem cells evade innate immune suppression of self-renewal through reduced TLR4 expression. Cell Stem Cell. 2017;20(4):450–461 e4.PubMedPubMedCentralCrossRef
84.
Herrmann A, Cherryholmes G, Schroeder A, Phallen J, Alizadeh D, Xin H, et al. TLR9 is critical for glioma stem cell maintenance and targeting. Cancer Res. 2014;74(18):5218–28.PubMedPubMedCentralCrossRef
85.
86.
Iribarren K, Bloy N, Buque A, Cremer I, Eggermont A, Fridman WH, et al. Trial watch: Immunostimulation with Toll-like receptor agonists in cancer therapy. Oncoimmunology. 2016;5(3):e1088631.PubMedCrossRef
87.
Chiang CL, Kandalaft LE, Coukos G. Adjuvants for enhancing the immunogenicity of whole tumor cell vaccines. Int Rev Immunol. 2011;30(2–3):150–82.PubMedCrossRef
88.
Mauldin IS, Wages NA, Stowman AM, Wang E, Olson WC, Deacon DH, et al. Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases. Cancer Immunol Immunother. 2016;65(10):1201–12.PubMedPubMedCentralCrossRef
89.
Tsuji S, Matsumoto M, Takeuchi O, Akira S, Azuma I, Hayashi A, et al. Maturation of human dendritic cells by cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guerin: involvement of Toll-like receptors. Infect Immun. 2000;68(12):6883–90.PubMedPubMedCentralCrossRef
90.
Bohle A, Brandau S. Immune mechanisms in bacillus Calmette-Guerin immunotherapy for superficial bladder cancer. J Urol. 2003;170(3):964–9.PubMedCrossRef
91.
Higuchi T, Shimizu M, Owaki A, Takahashi M, Shinya E, Nishimura T, et al. A possible mechanism of intravesical BCG therapy for human bladder carcinoma: involvement of innate effector cells for the inhibition of tumor growth. Cancer Immunol Immunother. 2009;58(8):1245–55.PubMedCrossRef
92.
Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180–3.CrossRefPubMed
93.
Shelley MD, Mason MD, Kynaston H. Intravesical therapy for superficial bladder cancer: a systematic review of randomised trials and meta-analyses. Cancer Treat Rev. 2010;36(3):195–205.PubMedCrossRef
94.
Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, et al. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional-cell carcinoma of the bladder. N Engl J Med. 1991;325(17):1205–9.PubMedCrossRef
95.
Brausi M, Oddens J, Sylvester R, Bono A, van de Beek C, van Andel G, et al. Side effects of Bacillus Calmette-Guerin (BCG) in the treatment of intermediate- and high-risk ta, T1 papillary carcinoma of the bladder: results of the EORTC genito-urinary cancers group randomised phase 3 study comparing one-third dose with full dose and 1 year with 3 years of maintenance BCG. Eur Urol. 2014;65(1):69–76.PubMedCrossRef
96.
Vermorken JB, Claessen AM, van Tinteren H, Gall HE, Ezinga R, Meijer S, et al. Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial. Lancet. 1999;353(9150):345–50.PubMedCrossRef
97.
Lotem M, Merims S, Frank S, Hamburger T, Nissan A, Kadouri L, et al. Adjuvant autologous melanoma vaccine for macroscopic stage III disease: survival, biomarkers, and improved response to CTLA-4 blockade. J Immunol Res. 2016;2016:8121985.PubMedPubMedCentralCrossRef
98.
99.
Derre L, Cesson V, Lucca I, Cerantola Y, Valerio M, Fritschi U, et al. Intravesical Bacillus Calmette Guerin combined with a cancer vaccine increases local T-cell responses in non-muscle-invasive bladder cancer patients. Clin Cancer Res. 2017;23(3):717–25.PubMedCrossRef
100.
Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol. 2004;50(5):722–33.PubMedCrossRef
101.
Arends TJ, Lammers RJ, Falke J, van der Heijden AG, Rustighini I, Pozzi R, et al. Pharmacokinetic, Pharmacodynamic, and activity evaluation of TMX-101 in a multicenter phase 1 study in patients with papillary non-muscle-invasive bladder cancer. Clin Genitourin Cancer. 2015;13(3):204–9 e2.PubMedCrossRef
102.
Drobits B, Holcmann M, Amberg N, Swiecki M, Grundtner R, Hammer M, et al. Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. J Clin Invest. 2012;122(2):575–85.PubMedPubMedCentralCrossRef
103.
Palamara F, Meindl S, Holcmann M, Luhrs P, Stingl G, Sibilia M. Identification and characterization of pDC-like cells in normal mouse skin and melanomas treated with imiquimod. J Immunol. 2004;173(5):3051–61.PubMedCrossRef
104.
Adams S, Kozhaya L, Martiniuk F, Meng TC, Chiriboga L, Liebes L, et al. Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer. Clin Cancer Res. 2012;18(24):6748–57.PubMedPubMedCentralCrossRef
105.
Martinez-Gonzalez MC, Verea-Hernando MM, Yebra-Pimentel MT, Del Pozo J, Mazaira M, Fonseca E. Imiquimod in mycosis fungoides. Eur J Dermatol. 2008;18(2):148–52.PubMed
106.
Adams S, O'Neill DW, Nonaka D, Hardin E, Chiriboga L, Siu K, et al. Immunization of malignant melanoma patients with full-length NY-ESO-1 protein using TLR7 agonist imiquimod as vaccine adjuvant. J Immunol. 2008;181(1):776–84.PubMedCrossRef
107.
Cantisani C, Lazic T, Richetta AG, Clerico R, Mattozzi C, Calvieri S. Imiquimod 5% cream use in dermatology, side effects and recent patents. Recent Patents Inflamm Allergy Drug Discov. 2012;6(1):65–9.CrossRef
108.
Alving CR, Rao M, Steers NJ, Matyas GR, Mayorov AV. Liposomes containing lipid A: an effective, safe, generic adjuvant system for synthetic vaccines. Expert Rev Vaccines. 2012;11(6):733–44.PubMedCrossRef
109.
Boland G, Beran J, Lievens M, Sasadeusz J, Dentico P, Nothdurft H, et al. Safety and immunogenicity profile of an experimental hepatitis B vaccine adjuvanted with AS04. Vaccine. 2004;23(3):316–20.PubMedCrossRef
110.
Bhatia S, Miller N, Lu H, Ibrani D, Shinohara S, Byrd D, et al. Pilot trial of intratumoral (IT) G100, a Toll-like receptor-4 (TLR4) agonist, in patients (pts) with Merkel cell carcinoma (MCC): final clinical results and immunologic effects on the tumor microenvironment (TME). J Clin Oncol. 2016;34(15__suppl):3021.CrossRef
111.
Cluff CW. Monophosphoryl lipid A (MPL) as an adjuvant for anti-cancer vaccines: clinical results. Adv Exp Med Biol. 2010;667:111–23.PubMedCrossRef
112.
Vansteenkiste JF, Cho BC, Vanakesa T, De Pas T, Zielinski M, Kim MS, et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(6):822–35.PubMedCrossRef
113.
Agarwala SS, Neuberg D, Park Y, Kirkwood JM. Mature results of a phase III randomized trial of bacillus Calmette-Guerin (BCG) versus observation and BCG plus dacarbazine versus BCG in the adjuvant therapy of American Joint Committee on Cancer stage I-III melanoma (E1673): a trial of the Eastern Oncology Group. Cancer. 2004;100(8):1692–8.PubMedCrossRef
114.
Salazar LG, Lu H, Reichow JL, Childs JS, Coveler AL, Higgins DM, et al. Topical Imiquimod plus nab-paclitaxel for breast cancer cutaneous metastases: a phase 2 clinical trial. JAMA Oncol. 2017;3(7):969–73.PubMedPubMedCentralCrossRef
115.
Meyer T, Surber C, French LE, Stockfleth E. Resiquimod, a topical drug for viral skin lesions and skin cancer. Expert Opin Investig Drugs. 2013;22(1):149–59.PubMedCrossRef
116.
Rook AH, Gelfand JM, Wysocka M, Troxel AB, Benoit B, Surber C, et al. Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma. Blood. 2015;126(12):1452–61.PubMedPubMedCentralCrossRef
117.
Sabado RL, Pavlick A, Gnjatic S, Cruz CM, Vengco I, Hasan F, et al. Resiquimod as an immunologic adjuvant for NY-ESO-1 protein vaccination in patients with high-risk melanoma. Cancer Immunol Res. 2015;3(3):278–87.PubMedPubMedCentralCrossRef
118.
119.
Krieg AM. Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene. 2008;27(2):161–7.PubMedCrossRef
120.
Kim YH, Girardi M, Duvic M, Kuzel T, Link BK, Pinter-Brown L, et al. Phase I trial of a Toll-like receptor 9 agonist, PF-3512676 (CPG 7909), in patients with treatment-refractory, cutaneous T-cell lymphoma. J Am Acad Dermatol. 2010;63(6):975–83.PubMedCrossRef
121.
Zent CS, Smith BJ, Ballas ZK, Wooldridge JE, Link BK, Call TG, et al. Phase I clinical trial of CpG oligonucleotide 7909 (PF-03512676) in patients with previously treated chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53(2):211–7.PubMedCrossRef
122.
Xing N, Qiao T, Zhuang X, Yuan S, Zhang Q, Xu G. CpG oligodeoxyribonucleotide 7909 enhances radiosensitivity via downregulating Oct-4 expression in radioresistant lung cancer cells. Onco Targets Ther. 2015;8:1443–9.PubMedPubMedCentralCrossRef
123.
Chen X, Zhang Q, Luo Y, Gao C, Zhuang X, Xu G, et al. High-dose irradiation in combination with Toll-like receptor 9 agonist CpG oligodeoxynucleotide 7909 downregulates PD-L1 expression via the NF-kappaB signaling pathway in non-small cell lung cancer cells. Onco Targets Ther. 2016;9:6511–8.PubMedPubMedCentralCrossRef
124.
Wang S, Campos J, Gallotta M, Gong M, Crain C, Naik E, et al. 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. 2016;113(46):E7240–9.PubMedPubMedCentral
125.
Martins KA, Bavari S, Salazar AM. Vaccine adjuvant uses of poly-IC and derivatives. Expert Rev Vaccines. 2015;14(3):447–59.PubMedCrossRef
126.
Ammi R, De Waele J, Willemen Y, Van Brussel I, Schrijvers DM, Lion E, et al. Poly(I:C) as cancer vaccine adjuvant: knocking on the door of medical breakthroughs. Pharmacol Ther. 2015;146:120–31.PubMedCrossRef
127.
Pollack IF, Jakacki RI, Butterfield LH, Hamilton RL, Panigrahy A, Normolle DP, et al. Immune responses and outcome after vaccination with glioma-associated antigen peptides and poly-ICLC in a pilot study for pediatric recurrent low-grade gliomas. Neuro-Oncology. 2016;18(8):1157–68.PubMedPubMedCentralCrossRef
128.
Rosenfeld MR, Chamberlain MC, Grossman SA, Peereboom DM, Lesser GJ, Batchelor TT, et al. A multi-institution phase II study of poly-ICLC and radiotherapy with concurrent and adjuvant temozolomide in adults with newly diagnosed glioblastoma. Neuro-Oncology. 2010;12(10):1071–7.PubMedPubMedCentralCrossRef
129.
Burdelya LG, Krivokrysenko VI, Tallant TC, Strom E, Gleiberman AS, Gupta D, et al. An agonist of Toll-like receptor 5 has radioprotective activity in mouse and primate models. Science. 2008;320(5873):226–30.PubMedPubMedCentralCrossRef
130.
Kojouharov BM, Brackett CM, Veith JM, Johnson CP, Gitlin II, Toshkov IA, et al. Toll-like receptor-5 agonist Entolimod broadens the therapeutic window of 5-fluorouracil by reducing its toxicity to normal tissues in mice. Oncotarget. 2014;5(3):802–14.PubMedPubMedCentralCrossRef
131.
Bakhribah H, Dy G, Ma W, Zhao Y, Opyrchal M, Purmal A, et al. A phase I study of the Toll-like receptor 5 (TLR5) agonist, entolimod in patients (pts) with advanced cancers. J Clin Oncol. 2015;33(15_suppl):3063.CrossRef
132.
Pandey RK, Sodhi A, Biswas SK, Dahiya Y, Dhillon MK. Mycobacterium indicus pranii mediates macrophage activation through TLR2 and NOD2 in a MyD88 dependent manner. Vaccine. 2012;30(39):5748–54.PubMedCrossRef
133.
Belani CP, Chakraborty BC, Modi RI, Khamar BM. A randomized trial of TLR-2 agonist CADI-05 targeting desmocollin-3 for advanced non-small-cell lung cancer. Ann Oncol. 2017;28(2):298–304.PubMedCrossRef
134.
Rakshit S, Ponnusamy M, Papanna S, Saha B, Ahmed A, Nandi D. Immunotherapeutic efficacy of Mycobacterium indicus pranii in eliciting anti-tumor T cell responses: critical roles of IFNγ. Int J Cancer. 2012;130(4):865–75.PubMedCrossRef
135.
Messaritakis I, Stogiannitsi M, Koulouridi A, Sfakianaki M, Voutsina A, Sotiriou A, et al. Evaluation of the detection of Toll-like receptors (TLRs) in cancer development and progression in patients with colorectal cancer. PLoS One. 2018;13(6):e0197327.PubMedPubMedCentralCrossRef
136.
Damiano V, Caputo R, Garofalo S, Bianco R, Rosa R, Merola G, et al. TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts. Proc Natl Acad Sci U S A. 2007;104(30):12468–73.PubMedPubMedCentralCrossRef
137.
Okazaki S, Stintzing S, Sunakawa Y, Cao S, Zhang W, Yang D, et al. Predictive value of TLR7 polymorphism for cetuximab-based chemotherapy in patients with metastatic colorectal cancer. Int J Cancer. 2017;141(6):1222–30.PubMedPubMedCentralCrossRef
138.
Milhem M, Gonzales R, Medina T, Kirkwood J, Buchbinder E, Mehmi I, et al. Intratumoral Toll-like receptor 9 (TLR9) agonist, CMP-001, in combination with pembrolizumab can reverse resistance to PD-1 inhibition in a phase Ib trial in subjects with advanced melanoma. Cancer Res. 2018. Abstract CT144.
139.
Takeda Y, Kataoka K, Yamagishi J, Ogawa S, Seya T, Matsumoto M. A TLR3-specific adjuvant relieves innate resistance to PD-L1 blockade without cytokine toxicity in tumor vaccine immunotherapy. Cell Rep. 2017;19(9):1874–87.PubMedCrossRef
140.
Sato-Kaneko F, Yao S, Ahmadi A, Zhang SS, Hosoya T, Kaneda MM, et al. Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer. JCI Insight. 2017;2(18).
141.
Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20(19):5064–74.PubMedPubMedCentralCrossRef
142.
Wimberly H, Brown JR, Schalper K, Haack H, Silver MR, Nixon C, et al. PD-L1 expression correlates with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy in breast cancer. Cancer Immunol Res. 2015;3(4):326–32.CrossRefPubMed
143.
Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16(11):2598–608.PubMedCrossRefPubMedCentral
144.
145.
Lai Y, Weng J, Wei X, Qin L, Lai P, Zhao R, et al. Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T cells. Leukemia. 2018;32(3):801–8.PubMedCrossRef
146.
Liu C. Toll-like receptor 2 deficiency enhances KRAS-driven lung cancer. Cancer Res. 2018. Abstract 4067.
147.
Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–8.PubMedPubMedCentralCrossRef
148.
Velazquez E, Lattin J, Brindley T, Reinstein Z, Chu R, Liu L, et al. Macrophage Toll-like receptor-chimeric antigen receptors (MOTO-CARs) as a novel adoptive cell therapy for the treatment of solid malignancies. Cancer Res. 2018. Abstract 2563.
149.
Banday AH, Jeelani S, Hruby VJ. Cancer vaccine adjuvants--recent clinical progress and future perspectives. Immunopharmacol Immunotoxicol. 2015;37(1):1–11.PubMedCrossRef
150.
Lesterhuis WJ, Haanen JB, Punt CJ. Cancer immunotherapy--revisited. Nat Rev Drug Discov. 2011;10(8):591–600.PubMedCrossRef
151.
Kyi C, Sabado R, Blazquez A, Posner M, Genden E, Miles B. A phase I study of the safety and immunogenicity of a multipeptide personalized genomic vaccine in the adjuvant treatment of solid cancers. J Clin Oncol. 2017;35(15_suppl):3114.CrossRef
152.
Dillon PM, Petroni GR, Smolkin ME, Brenin DR, Chianese-Bullock KA, Smith KT, et al. A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus poly-ICLC in early stage breast cancer. J Immunother Cancer. 2017;5(1):92.PubMedPubMedCentralCrossRef
153.
Ilyinskii PO, Kovalev GI, O'Neil CP, Roy CJ, Michaud AM, Drefs NM, et al. Synthetic vaccine particles for durable cytolytic T lymphocyte responses and anti-tumor immunotherapy. PLoS One. 2018;13(6):e0197694.PubMedPubMedCentralCrossRef
154.
Wang JQ, Jeelall YS, Ferguson LL, Horikawa K. Toll-like receptors and cancer: MYD88 mutation and inflammation. Front Immunol. 2014;5:367.PubMedPubMedCentral
155.
Treon SP, Xu L, Hunter Z. MYD88 mutations and response to Ibrutinib in Waldenstrom's Macroglobulinemia. N Engl J Med. 2015;373(6):584–6.PubMedCrossRef
156.
Phelan JD, Young RM, Webster DE, Roulland S, Wright GW, Kasbekar M, et al. A multiprotein supercomplex controlling oncogenic signalling in lymphoma. Nature. 2018;560(7718):387-91.PubMedCrossRefPubMedCentral
157.
Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470(7332):115–9.PubMedCrossRef
158.
Zhang D, Li L, Jiang H, Knolhoff BL, Lockhart AC, Wang-Gillam A, et al. Constitutive IRAK4 activation underlies poor prognosis and Chemoresistance in pancreatic ductal adenocarcinoma. Clin Cancer Res. 2017;23(7):1748–59.PubMedCrossRef
159.
Choudhary G, Bhagat T, Samson M, Gordon S, Ahrens D, Pradhan K, et al. Efficacy of novel IRAK4 inhibitor CA4948 in AML and MDS. Cancer Res. 2017. Abstract 127.
160.
Kluwe J, Mencin A, Schwabe RF. Toll-like receptors, wound healing, and carcinogenesis. J Mol Med (Berl). 2009;87(2):125–38.CrossRef
161.
Burdelya LG, Gleiberman AS, Toshkov I, Aygun-Sunar S, Bapardekar M, Manderscheid-Kern P, et al. Toll-like receptor 5 agonist protects mice from dermatitis and oral mucositis caused by local radiation: implications for head-and-neck cancer radiotherapy. Int J Radiat Oncol Biol Phys. 2012;83(1):228–34.PubMedCrossRef
162.
Burdelya LG, Brackett CM, Kojouharov B, Gitlin II, Leonova KI, Gleiberman AS, et al. Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist. Proc Natl Acad Sci U S A. 2013;110(20):E1857–66.PubMedPubMedCentralCrossRef
163.
Frank M, Hennenberg EM, Eyking A, Runzi M, Gerken G, Scott P, et al. TLR signaling modulates side effects of anticancer therapy in the small intestine. J Immunol. 2015;194(4):1983–95.PubMedCrossRef
164.
Pushalkar S, Hundeyin M, Daley D, Zambirinis CP, Kurz E, Mishra A, et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 2018;8(4):403–16.PubMedCrossRefPubMedCentral
165.
Taylor PA, Ehrhardt MJ, Lees CJ, Panoskaltsis-Mortari A, Krieg AM, Sharpe AH, et al. TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection. Blood. 2008;112(8):3508–16.PubMedPubMedCentralCrossRef
166.
Kornblit B, Muller K. Sensing danger: Toll-like receptors and outcome in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2017;52(4):499–505.PubMedCrossRef
167.
Elmaagacli AH, Koldehoff M, Beelen DW. Improved outcome of hematopoietic SCT in patients with homozygous gene variant of Toll-like receptor 9. Bone Marrow Transplant. 2009;44(5):295–302.PubMedCrossRef
Metadata
Title
Targeting Toll-Like Receptors for Cancer Therapy
Authors
Marc J. Braunstein
John Kucharczyk
Sylvia Adams
Publication date
01-10-2018
Publisher
Springer International Publishing
Published in
Targeted Oncology / Issue 5/2018
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-018-0589-7

Other articles of this Issue 5/2018

Targeted Oncology 5/2018 Go to the issue

Editorial

Tumor Type-Agnostic Treatment and the Future of Cancer Therapy

Original Research Article

Immediate Progressive Disease in Patients with Metastatic Renal Cell Carcinoma Treated with Nivolumab: a Multi-Institution Retrospective Study

Original Research Article

Characteristics and Response to Crizotinib in ALK-Rearranged, Advanced Non-Adenocarcinoma, Non-Small Cell Lung Cancer (NA-NSCLC) Patients: a Retrospective Study and Literature Review

Correction

Correction to: Medical Treatment Options for Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer Suffering from Brain Metastases and/or Leptomeningeal Disease

Review Article

Targeted Therapies in the Treatment of Sarcomas

Original Research Article

EGFR Amplification and Sensitizing Mutations Correlate with Survival in Lung Adenocarcinoma Patients Treated with Erlotinib (MutP-CLICaP)
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits