Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

IMPACT FACTOR 2018: 3.014
5-year IMPACT FACTOR: 3.162

CiteScore 2018: 3.09

SCImago Journal Rank (SJR) 2018: 1.482
Source Normalized Impact per Paper (SNIP) 2018: 0.820

See all formats and pricing
More options …
Ahead of print


Developments in anticancer vaccination: budding new adjuvants

Sandra Santos-SierraORCID iD: https://orcid.org/0000-0002-4691-3003
Published Online: 2019-12-13 | DOI: https://doi.org/10.1515/hsz-2019-0383


The immune system has a limited capacity to recognize and fight cells that become cancerous and in cancer patients, the immune system has to seek the right balance between cancer rejection and host-immunosupression. The tumor milieu builds a protective shell and tumor cells rapidly accumulate mutations that promote antigen variability and immune-escape. Therapeutic vaccination of cancer is a promising strategy the success of which depends on a powerful activation of the cells of the adaptive immune system specific for tumor-cell detection and killing (e.g. CD4+ and CD8+ T-cells). In the last decades, the search for novel adjuvants that enhance dendritic cell (DC) function and their ability to prime T-cells has flourished and some Toll-like receptor (TLR) agonists have long been known to be valid immune adjuvants. The implementation of TLR-synthetic agonists in clinical studies of cancer vaccination is replacing the initial use of microbial-derived products with some encouraging results. The purpose of this review is to summarize the latest discoveries of TLR-synthetic agonists with adjuvant potential in anti-cancer vaccination.

Keywords: adjuvant; agonist; cancer vaccination; Toll-like receptor


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

  • Aliprantis, A.O., Yang, R.B., Mark, M.R., Suggett, S., Devaux, B., Radolf, J.D., Klimpel, G.R., Godowski, P., and Zychlinsky, A. (1999). Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 285, 736–739.CrossrefPubMedGoogle Scholar

  • Balkwill, F. and Mantovani, A. (2001). Inflammation and cancer: back to Virchow? Lancet 357, 539–545.PubMedCrossrefGoogle Scholar

  • Bauer, S., Kirschning, C.J., Hacker, H., Redecke, V., Hausmann, S., Akira, S., Wagner, H., and Lipford, G.B. (2001). Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc. Natl. Acad. Sci. U.S.A. 98, 9237–9242.CrossrefPubMedGoogle Scholar

  • Bezu, L., Kepp, O., Cerrato, G., Pol, J., Fucikova, J., Spisek, R., Zitvogel, L., Kroemer, G., and Galluzzi, L. (2018). Trial watch: peptide-based vaccines in anticancer therapy. Oncoimmunology 7, e1511506.CrossrefPubMedGoogle Scholar

  • Bianchi, F., Pretto, S., Tagliabue, E., Balsari, A., and Sfondrini, L. (2017). Exploiting poly(I:C) to induce cancer cell apoptosis. Cancer Biol. Ther. 18, 747–756.PubMedCrossrefGoogle Scholar

  • Biassoni, R., Cantoni, C., Pende, D., Sivori, S., Parolini, S., Vitale, M., Bottino, C., and Moretta, A. (2001). Human natural killer cell receptors and co-receptors. Immunol. Rev. 181, 203–214.CrossrefPubMedGoogle Scholar

  • Blander, J.M. (2018). Regulation of the cell biology of antigen cross-presentation. Annu. Rev. Immunol. 36, 717–753.PubMedCrossrefGoogle Scholar

  • Bloy, N., Pol, J., Aranda, F., Eggermont, A., Cremer, I., Fridman, W.H., Fucikova, J., Galon, J., Tartour, E., Spisek, R., et al. (2014). Trial watch: dendritic cell-based anticancer therapy. Oncoimmunology 3, e963424.CrossrefPubMedGoogle Scholar

  • Bocanegra Gondan, A.I., Ruiz-de-Angulo, A., Zabaleta, A., Gomez Blanco, N., Cobaleda-Siles, B.M., Garcia-Granda, M.J., Padro, D., Llop, J., Arnaiz, B., Gato, M., et al. (2018). Effective cancer immunotherapy in mice by polyIC-imiquimod complexes and engineered magnetic nanoparticles. Biomaterials 170, 95–115.CrossrefPubMedGoogle Scholar

  • Bohle, A. and Brandau, S. (2003). Immune mechanisms in bacillus Calmette-Guerin immunotherapy for superficial bladder cancer. J. Urol. 170, 964–969.PubMedCrossrefGoogle Scholar

  • Brackett, C.M., Kojouharov, B., Veith, J., Greene, K.F., Burdelya, L.G., Gollnick, S.O., Abrams, S.I., and Gudkov, A.V. (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, E874–E883.PubMedCrossrefGoogle Scholar

  • Bright, R.K., Bright, J.D., and Byrne, J.A. (2014). Overexpressed oncogenic tumor-self antigens. Hum. Vaccin. Immunother. 10, 3297–3305.CrossrefPubMedGoogle Scholar

  • Brodsky, I., Strayer, D.R., Krueger, L.J., and Carter, W.A. (1985). Clinical studies with ampligen (mismatched double-stranded RNA). J. Biol. Response Mod. 4, 669–675.PubMedGoogle Scholar

  • Burdelya, L.G., Krivokrysenko, V.I., Tallant, T.C., Strom, E., Gleiberman, A.S., Gupta, D., Kurnasov, O.V., Fort, F.L., Osterman, A.L., Didonato, J.A., et al. (2008). An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 320, 226–230.CrossrefPubMedGoogle Scholar

  • Cheever, M.A., Allison, J.P., Ferris, A.S., Finn, O.J., Hastings, B.M., Hecht, T.T., Mellman, I., Prindiville, S.A., Viner, J.L., Weiner, L.M., et al. (2009). The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin. Cancer Res. 15, 5323–5337.PubMedCrossrefGoogle Scholar

  • Choe, J., Kelker, M.S., and Wilson, I.A. (2005). Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science 309, 581–585.CrossrefPubMedGoogle Scholar

  • Church, J.S., Milich, L.M., Lerch, J.K., Popovich, P.G., and McTigue, D.M. (2017). E6020, a synthetic TLR4 agonist, accelerates myelin debris clearance, Schwann cell infiltration, and remyelination in the rat spinal cord. Glia 65, 883–899.PubMedCrossrefGoogle Scholar

  • Coulie, P.G., Van den Eynde, B.J., van der Bruggen, P., and Boon, T. (2014). Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat. Rev. Cancer 14, 135–146.CrossrefGoogle Scholar

  • Didierlaurent, A.M., Morel, S., Lockman, L., Giannini, S.L., Bisteau, M., Carlsen, H., Kielland, A., Vosters, O., Vanderheyde, N., Schiavetti, F., et al. (2009). AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J. Immunol. 183, 6186–6197.CrossrefPubMedGoogle Scholar

  • Diebold, S.S., Kaisho, T., Hemmi, H., Akira, S., and Reis e Sousa, C. (2004). Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531.CrossrefPubMedGoogle Scholar

  • Droemann, D., Albrecht, D., Gerdes, J., Ulmer, A.J., Branscheid, D., Vollmer, E., Dalhoff, K., Zabel, P., and Goldmann, T. (2005). Human lung cancer cells express functionally active Toll-like receptor 9. Respir. Res. 6, 1.PubMedCrossrefGoogle Scholar

  • Du, X., Qian, J., Wang, Y., Zhang, M., Chu, Y., and Li, Y. (2019). Identification and immunological evaluation of novel TLR2 agonists through structure optimization of Pam3CSK4. Bioorg. Med. Chem. 27, 2784–2800.PubMedCrossrefGoogle Scholar

  • Dubensky Jr, T.W. and Reed, S.G. (2010). Adjuvants for cancer vaccines. Semin. Immunol. 22, 155–161.CrossrefPubMedGoogle Scholar

  • Dunn, G.P., Bruce, A.T., Ikeda, H., Old, L.J., and Schreiber, R.D. (2002). Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998.CrossrefPubMedGoogle Scholar

  • Erridge, C. (2010). Endogenous ligands of TLR2 and TLR4: agonists or assistants? J. Leukoc. Biol. 87, 989–999.CrossrefPubMedGoogle Scholar

  • Faham, A. and Altin, J.G. (2010). Antigen-containing liposomes engrafted with flagellin-related peptides are effective vaccines that can induce potent antitumor immunity and immunotherapeutic effect. J. Immunol. 185, 1744–1754.PubMedCrossrefGoogle Scholar

  • Garaude, J., Kent, A., van Rooijen, N., and Blander, J.M. (2012). Simultaneous targeting of toll- and nod-like receptors induces effective tumor-specific immune responses. Sci. Transl. Med. 4, 120ra116.Google Scholar

  • Gerard, C., Baudson, N., Ory, T., and Louahed, J. (2014). Tumor mouse model confirms MAGE-A3 cancer immunotherapeutic as an efficient inducer of long-lasting anti-tumoral responses. PLoS One 9, e94883.PubMedCrossrefGoogle Scholar

  • Gorden, K.B., Gorski, K.S., Gibson, S.J., Kedl, R.M., Kieper, W.C., Qiu, X., Tomai, M.A., Alkan, S.S., and Vasilakos, J.P. (2005). Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J. Immunol. 174, 1259–1268.PubMedCrossrefGoogle Scholar

  • Guan, Y., Omueti-Ayoade, K., Mutha, S.K., Hergenrother, P.J., and Tapping, R.I. (2010). Identification of novel synthetic toll-like receptor 2 agonists by high throughput screening. J. Biol. Chem. 285, 23755–23762.CrossrefPubMedGoogle Scholar

  • Gulley, J.L., Madan, R.A., Pachynski, R., Mulders, P., Sheikh, N.A., Trager, J., and Drake, C.G. (2017). Role of antigen spread and distinctive characteristics of immunotherapy in cancer treatment. J. Natl. Cancer Inst. 109.PubMedGoogle Scholar

  • Gungor, B., Yagci, F.C., Gursel, I., and Gursel, M. (2014). Forging a potent vaccine adjuvant: CpG ODN/cationic peptide nanorings. Oncoimmunology 3, e950166.CrossrefPubMedGoogle Scholar

  • Gutjahr, A., Papagno, L., Nicoli, F., Lamoureux, A., Vernejoul, F., Lioux, T., Gostick, E., Price, D.A., Tiraby, G., Perouzel, E., et al. (2017). Cutting edge: a dual TLR2 and TLR7 ligand induces highly potent humoral and cell-mediated immune responses. J. Immunol. 198, 4205–4209.CrossrefGoogle Scholar

  • Hamm, S., Rath, S., Michel, S., and Baumgartner, R. (2009). Cancer immunotherapeutic potential of novel small molecule TLR7 and TLR8 agonists. J. Immunotoxicol. 6, 257–265.PubMedCrossrefGoogle Scholar

  • Harrison, L.I., Astry, C., Kumar, S., and Yunis, C. (2007). Pharmacokinetics of 852A, an imidazoquinoline Toll-like receptor 7-specific agonist, following intravenous, subcutaneous, and oral administrations in humans. J. Clin. Pharmacol. 47, 962–969.CrossrefPubMedGoogle Scholar

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

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

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

  • Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., et al. (2000). A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745.CrossrefPubMedGoogle Scholar

  • Hemmi, H., Kaisho, T., Takeuchi, O., Sato, S., Sanjo, H., Hoshino, K., Horiuchi, T., Tomizawa, H., Takeda, K., and Akira, S. (2002). Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3, 196–200.CrossrefPubMedGoogle Scholar

  • Hemont, C., Neel, A., Heslan, M., Braudeau, C., and Josien, R. (2013). Human blood mDC subsets exhibit distinct TLR repertoire and responsiveness. J. Leukoc. Biol. 93, 599–609.CrossrefPubMedGoogle Scholar

  • Herrera, F.G., Bourhis, J., and Coukos, G. (2017). Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J. Clin. 67, 65–85.CrossrefPubMedGoogle Scholar

  • Holko, P. and Kawalec, P. (2014). Economic evaluation of sipuleucel-T immunotherapy in castration-resistant prostate cancer. Expert Rev. Anticancer Ther. 14, 63–73.CrossrefPubMedGoogle Scholar

  • Hornung, V., Rothenfusser, S., Britsch, S., Krug, A., Jahrsdorfer, B., Giese, T., Endres, S., and Hartmann, G. (2002). Quantitative expression of toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J. Immunol. 168, 4531–4537.PubMedCrossrefGoogle Scholar

  • Hornung, V., Guenthner-Biller, M., Bourquin, C., Ablasser, A., Schlee, M., Uematsu, S., Noronha, A., Manoharan, M., Akira, S., de Fougerolles, A., et al. (2005). Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat. Med. 11, 263–270.CrossrefPubMedGoogle Scholar

  • Huleatt, J.W., Jacobs, A.R., Tang, J., Desai, P., Kopp, E.B., Huang, Y., Song, L., Nakaar, V., and Powell, T.J. (2007). Vaccination with recombinant fusion proteins incorporating Toll-like receptor ligands induces rapid cellular and humoral immunity. Vaccine 25, 763–775.PubMedCrossrefGoogle Scholar

  • Hussein, W.M., Liu, T.Y., Skwarczynski, M., and Toth, I. (2014). Toll-like receptor agonists: a patent review (2011–2013). Expert Opin. Ther. Pat. 24, 453–470.CrossrefPubMedGoogle Scholar

  • Iurescia, S., Fioretti, D., and Rinaldi, M. (2018). Targeting cytosolic nucleic acid-sensing pathways for cancer immunotherapies. Front. Immunol. 9, 711.PubMedCrossrefGoogle Scholar

  • Janeway Jr, C.A. and Medzhitov, R. (2002). Innate immune recognition. Annu. Rev. Immunol. 20, 197–216.PubMedCrossrefGoogle Scholar

  • Jin, M.S., Kim, S.E., Heo, J.Y., Lee, M.E., Kim, H.M., Paik, S.G., Lee, H., and Lee, J.O. (2007). Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 130, 1071–1082.PubMedCrossrefGoogle Scholar

  • Johnson, R.S., Walker, A.I., and Ward, S.J. (2009). Cancer vaccines: will we ever learn? Expert. Rev. Anticancer Ther. 9, 67–74.CrossrefPubMedGoogle Scholar

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

  • Kaur, A.P., Patil, M.T., Mehta, S.K., and Salunke, D.B. (2018). An efficient and scalable synthesis of potent TLR2 agonistic PAM2CSK4. RSC Adv. 8, 9587–9596.CrossrefGoogle Scholar

  • Kim, H.M., Park, B.S., Kim, J.I., Kim, S.E., Lee, J., Oh, S.C.,Enkhbayar, P., Matsushima, N., Lee, H., Yoo, O.J., et al. (2007). Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell 130, 906–917.CrossrefPubMedGoogle Scholar

  • Kim, B.K., Han, K.H., and Ahn, S.H. (2011). Prevention of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. Oncology 81 (Suppl. 1), 41–49.PubMedCrossrefGoogle Scholar

  • Kim, J.Y., Park, J.H., Seo, S.M., Park, J.I., Jeon, H.Y., Lee, H.K., Yoo, R.J., Lee, Y.J., Woo, S.K., Lee, W.J., et al. (2019). Radioprotective effect of newly synthesized toll-like receptor 5 agonist, KMRC011, in mice exposed to total-body irradiation. J. Radiat. Res. 60, 432–441.CrossrefPubMedGoogle Scholar

  • Klebanoff, C.A., Gattinoni, L., and Restifo, N.P. (2006). CD8+ T-cell memory in tumor immunology and immunotherapy. Immunol. Rev. 211, 214–224.CrossrefPubMedGoogle Scholar

  • Kleef, R., Jonas, W.B., Knogler, W., and Stenzinger, W. (2001). Fever, cancer incidence and spontaneous remissions. Neuroimmunomodulation 9, 55–64.PubMedCrossrefGoogle Scholar

  • Krieg, A.M. (2007). Development of TLR9 agonists for cancer therapy. J. Clin. Invest. 117, 1184–1194.CrossrefPubMedGoogle Scholar

  • Levine, A.S., Sivulich, M., Wiernik, P.H., and Levy, H.B. (1979). Initial clinical trials in cancer patients of polyriboinosinic-polyribocytidylic acid stabilized with poly-L-lysine, in carboxymethylcellulose [poly(ICLC)], a highly effective interferon inducer. Cancer Res. 39, 1645–1650.PubMedGoogle Scholar

  • Levy, H.B., Baer, G., Baron, S., Buckler, C.E., Gibbs, C.J., Iadarola, M.J., London, W.T., and Rice, J. (1975). A modified polyriboinosinic-polyribocytidylic acid complex that induces interferon in primates. J. Infect. Dis. 132, 434–439.PubMedCrossrefGoogle Scholar

  • Liu, J.K. (2014). Anti-cancer vaccines – a one-hit wonder? Yale J. Biol. Med. 87, 481–489.PubMedGoogle Scholar

  • Lu, H. (2014). TLR agonists for cancer immunotherapy: tipping the balance between the immune stimulatory and inhibitory effects. Front. Immunol. 5, 83.PubMedGoogle Scholar

  • Lu, B., Williams, G.M., Verdon, D., Dunbar, P.R., and Brimble, M.A. (2019). Synthesis and evaluation of novel TLR2 agonists as potential adjuvants for cancer vaccines. J. Med. Chem., DOI: 10.1021/acs.jmedchem.9b01044 [epub ahead of print].PubMedGoogle Scholar

  • Masuta, Y., Yamamoto, T., Natsume-Kitatani, Y., Kanuma, T., Moriishi, E., Kobiyama, K., Mizuguchi, K., Yasutomi, Y., and Ishii, K.J. (2018). An antigen-free, plasmacytoid dendritic cell-targeting immunotherapy to bolster memory CD8+ T cells in nonhuman primates. J. Immunol. 200, 2067–2075.PubMedCrossrefGoogle Scholar

  • Matsumoto, M., Tatematsu, M., Nishikawa, F., Azuma, M., Ishii, N., Morii-Sakai, A., Shime, H., and Seya, T. (2015). Defined TLR3-specific adjuvant that induces NK and CTL activation without significant cytokine production in vivo. Nat. Commun. 6, 6280.CrossrefPubMedGoogle Scholar

  • McEwen, J., Levi, R., Horwitz, R.J., and Arnon, R. (1992). Synthetic recombinant vaccine expressing influenza haemagglutinin epitope in Salmonella flagellin leads to partial protection in mice. Vaccine 10, 405–411.CrossrefPubMedGoogle Scholar

  • Milosevic, S. (2019). Controlled cytotoxicity of tumor-specific TCR-modified T cells with improved avidity through control of TCR surface expression. In: CAR-TCR Summit (Medigene: Boston).Google Scholar

  • Morin, M.D., Wang, Y., Jones, B.T., Mifune, Y., Su, L., Shi, H., Moresco, E.M.Y., Zhang, H., Beutler, B., and Boger, D.L. (2018). Diprovocims: a new and exceptionally potent class of toll-like receptor agonists. J. Am. Chem. Soc. 140, 14440–14454.CrossrefPubMedGoogle Scholar

  • Murgueitio, M.S., Ebner, S., Hortnagl, P., Rakers, C., Bruckner, R., Henneke, P., Wolber, G., and Santos-Sierra, S. (2017). Enhanced immunostimulatory activity of in silico discovered agonists of Toll-like receptor 2 (TLR2). Biochim. Biophys. Acta. Gen. Subj. 1861, 2680–2689.PubMedCrossrefGoogle Scholar

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

  • Nguyen, C.T., Hong, S.H., Sin, J.I., Vu, H.V., Jeong, K., Cho, K.O., Uematsu, S., Akira, S., Lee, S.E., and Rhee, J.H. (2013). Flagellin enhances tumor-specific CD8+ T cell immune responses through TLR5 stimulation in a therapeutic cancer vaccine model. Vaccine 31, 3879–3887.CrossrefGoogle Scholar

  • Ohto, U., Shibata, T., Tanji, H., Ishida, H., Krayukhina, E., Uchiyama, S., Miyake, K., and Shimizu, T. (2015). Structural basis of CpG and inhibitory DNA recognition by Toll-like receptor 9. Nature 520, 702–705.PubMedCrossrefGoogle Scholar

  • Okemoto, K., Kawasaki, K., Hanada, K., Miura, M., and Nishijima, M. (2006). A potent adjuvant monophosphoryl lipid A triggers various immune responses, but not secretion of IL-1β or activation of caspase-1. J. Immunol. 176, 1203–1208.PubMedCrossrefGoogle Scholar

  • Overwijk, W.W. (2005). Breaking tolerance in cancer immunotherapy: time to ACT. Curr. Opin. Immunol. 17, 187–194.CrossrefPubMedGoogle Scholar

  • Overwijk, W.W. (2017). Cancer vaccines in the era of checkpoint blockade: the magic is in the adjuvant. Curr. Opin. Immunol. 47, 103–109.PubMedCrossrefGoogle Scholar

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

  • Panda, A.K. (2011). Induction of anti-tumor immunity and T-cell responses using nanodelivery systems engrafting TLR-5 ligand. Expert Rev. Vaccines 10, 155–157.PubMedCrossrefGoogle Scholar

  • Paone, A., Galli, R., Gabellini, C., Lukashev, D., Starace, D., Gorlach, A., De Cesaris, P., Ziparo, E., Del Bufalo, D., Sitkovsky, M.V., et al. (2010). Toll-like receptor 3 regulates angiogenesis and apoptosis in prostate cancer cell lines through hypoxia-inducible factor 1α. Neoplasia 12, 539–549.CrossrefGoogle Scholar

  • Piccinini, A.M. and Midwood, K.S. (2010). DAMPening inflammation by modulating TLR signalling. Mediat. Inflamm. 2010, 17–37Google Scholar

  • Poltorak, A., He, X., Smirnova, I., Liu, M.Y., Van Huffel, C., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., et al. (1998). Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088.PubMedCrossrefGoogle Scholar

  • Qureshi, N., Takayama, K., and Ribi, E. (1982). Purification and structural determination of nontoxic lipid A obtained from the lipopolysaccharide of Salmonella typhimurium. J. Biol. Chem. 257, 11808–11815.PubMedGoogle Scholar

  • Rakoff-Nahoum, S. and Medzhitov, R. (2009). Toll-like receptors and cancer. Nat. Rev. Cancer 9, 57–63.CrossrefGoogle Scholar

  • Redelman-Sidi, G., Glickman, M.S., and Bochner, B.H. (2014). The mechanism of action of BCG therapy for bladder cancer – a current perspective. Nat. Rev. Urol. 11, 153–162.CrossrefPubMedGoogle Scholar

  • Ribas, A., Medina, T., Kummar, S., Amin, A., Kalbasi, A., Drabick, J.J., Barve, M., Daniels, G.A., Wong, D.J., Schmidt, E.V., et al. (2018). SD-101 in combination with Pembrolizumab in advanced melanoma: results of a phase ib, multicenter study. Cancer Discov. 8, 1250–1257.PubMedCrossrefGoogle Scholar

  • Roden, R.B.S. and Stern, P.L. (2018). Opportunities and challenges for human papillomavirus vaccination in cancer. Nat. Rev. Cancer 18, 240–254.CrossrefPubMedGoogle Scholar

  • Salaun, B., Coste, I., Rissoan, M.C., Lebecque, S.J., and Renno, T. (2006). TLR3 can directly trigger apoptosis in human cancer cells. J. Immunol. 176, 4894–4901.CrossrefPubMedGoogle Scholar

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

  • Salgia, R., Lynch, T., Skarin, A., Lucca, J., Lynch, C., Jung, K., Hodi, F.S., Jaklitsch, M., Mentzer, S., Swanson, S., et al. (2003). Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma. J. Clin. Oncol. 21, 624–630.PubMedCrossrefGoogle Scholar

  • Santone, M., Aprea, S., Wu, T.Y., Cooke, M.P., Mbow, M.L., Valiante, N.M., Rush, J.S., Dougan, S., Avalos, A., Ploegh, H., et al. (2015). A new TLR2 agonist promotes cross-presentation by mouse and human antigen presenting cells. Hum. Vaccin. Immunother. 11, 2038–2050.PubMedCrossrefGoogle Scholar

  • Savage, P., Horton, V., Moore, J., Owens, M., Witt, P., and Gore, M.E. (1996). A phase I clinical trial of imiquimod, an oral interferon inducer, administered daily. Br. J. Cancer 74, 1482–1486.PubMedCrossrefGoogle Scholar

  • Schreibelt, G., Tel, J., Sliepen, K.H., Benitez-Ribas, D., Figdor, C.G., Adema, G.J., and de Vries, I.J. (2010). Toll-like receptor expression and function in human dendritic cell subsets: implications for dendritic cell-based anti-cancer immunotherapy. Cancer Immunol. Immunother. 59, 1573–1582.CrossrefPubMedGoogle Scholar

  • Seya, T., Takeda, Y., and Matsumoto, M. (2019). A Toll-like receptor 3 (TLR3) agonist ARNAX for therapeutic immunotherapy. Adv. Drug Deliv. Rev. 147, 37–43PubMedCrossrefGoogle Scholar

  • Sharma, P. and Allison, J.P. (2015). Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214.PubMedCrossrefGoogle Scholar

  • Shibata, K., Hasebe, A., Into, T., Yamada, M., and Watanabe, T. (2000). The N-terminal lipopeptide of a 44-kDa membrane-bound lipoprotein of Mycoplasma salivarium is responsible for the expression of intercellular adhesion molecule-1 on the cell surface of normal human gingival fibroblasts. J. Immunol. 165, 6538–6544.CrossrefGoogle Scholar

  • Silva, A., Mount, A., Krstevska, K., Pejoski, D., Hardy, M.P., Owczarek, C., Scotney, P., Maraskovsky, E., and Baz Morelli, A. (2015). The combination of ISCOMATRIX adjuvant and TLR agonists induces regression of established solid tumors in vivo. J. Immunol. 194, 2199–2207.CrossrefPubMedGoogle Scholar

  • Smith, M., Garcia-Martinez, E., Pitter, M.R., Fucikova, J., Spisek, R., Zitvogel, L., Kroemer, G., and Galluzzi, L. (2018). Trial Watch: Toll-like receptor agonists in cancer immunotherapy. Oncoimmunology 7, e1526250.PubMedCrossrefGoogle Scholar

  • Sosman, J.A. and Sondak, V.K. (2003). Melacine: an allogeneic melanoma tumor cell lysate vaccine. Expert Rev. Vaccines 2, 353–368.CrossrefPubMedGoogle Scholar

  • Starnes, C.O. (1992). Coley’s toxins in perspective. Nature 357, 11–12.CrossrefPubMedGoogle Scholar

  • Stockfleth, E., Trefzer, U., Garcia-Bartels, C., Wegner, T., Schmook, T., and Sterry, W. (2003). The use of Toll-like receptor-7 agonist in the treatment of basal cell carcinoma: an overview. Br. J. Dermatol. 149 (Suppl.) 66, 53–56.PubMedCrossrefGoogle Scholar

  • Su, L., Wang, Y., Wang, J., Mifune, Y., Morin, M.D., Jones, B.T., Moresco, E.M.Y., Boger, D.L., Beutler, B., and Zhang, H. (2019). Structural basis of TLR2/TLR1 activation by the synthetic agonist diprovocim. J. Med. Chem. 62, 2938–2949.CrossrefPubMedGoogle Scholar

  • Takeuchi, O., Kaufmann, A., Grote, K., Kawai, T., Hoshino, K., Morr, M., Muhlradt, P.F., and Akira, S. (2000). Cutting edge: preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a toll-like receptor 2- and MyD88-dependent signaling pathway. J. Immunol. 164, 554–557.PubMedCrossrefGoogle Scholar

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

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

  • Tandon, A., Pathak, M., Harioudh, M.K., Ahmad, S., Sayeed, M., Afshan, T., Siddiqi, M.I., Mitra, K., Bhattacharya, S.M., and Ghosh, J.K. (2018). A TLR4-derived non-cytotoxic, self-assembling peptide functions as a vaccine adjuvant in mice. J. Biol. Chem. 293, 19874–19885.PubMedCrossrefGoogle Scholar

  • Tanji, H., Ohto, U., Shibata, T., Miyake, K., and Shimizu, T. (2013). Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands. Science 339, 1426–1429.CrossrefPubMedGoogle Scholar

  • Temizoz, B., Kuroda, E., and Ishii, K.J. (2016). Vaccine adjuvants as potential cancer immunotherapeutics. Int. Immunol. 28, 329–338.PubMedCrossrefGoogle Scholar

  • Uematsu, S., Jang, M.H., Chevrier, N., Guo, Z., Kumagai, Y.,Yamamoto, M., Kato, H., Sougawa, N., Matsui, H., Kuwata, H., et al. (2006). Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells. Nat. Immunol. 7, 868–874.PubMedCrossrefGoogle Scholar

  • van der Burg, S.H., Arens, R., Ossendorp, F., van Hall, T., and Melief, C.J. (2016). Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nat. Rev. Cancer 16, 219–233.CrossrefPubMedGoogle Scholar

  • Vanella, V., Festino, L., Strudel, M., Simeone, E., Grimaldi, A.M., and Ascierto, P.A. (2017). PD-L1 inhibitors in the pipeline: promise and progress. Oncoimmunology 7, e1365209.PubMedGoogle Scholar

  • Vanpouille-Box, C., Lhuillier, C., Bezu, L., Aranda, F., Yamazaki, T., Kepp, O., Fucikova, J., Spisek, R., Demaria, S., Formenti, S.C., et al. (2017). Trial watch: immune checkpoint blockers for cancer therapy. Oncoimmunology 6, e1373237.CrossrefPubMedGoogle Scholar

  • Wang, H., Rayburn, E., and Zhang, R. (2005). Synthetic oligodeoxynucleotides containing deoxycytidyl-deoxyguanosine dinucleotides (CpG ODNs) and modified analogs as novel anticancer therapeutics. Curr. Pharm. Des. 11, 2889–2907.PubMedCrossrefGoogle Scholar

  • Wang, S., Campos, J., Gallotta, M., Gong, M., Crain, C., Naik, E., Coffman, R.L., and Guiducci, C. (2016a). 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, E7240–E7249.CrossrefGoogle Scholar

  • Wang, Y., Su, L., Morin, M.D., Jones, B.T., Whitby, L.R., Surakattula, M.M., Huang, H., Shi, H., Choi, J.H., Wang, K.W., et al. (2016b). TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS. Proc. Natl. Acad. Sci. U.S.A. 113, E884–893.CrossrefGoogle Scholar

  • Wang, Y., Su, L., Morin, M.D., Jones, B.T., Mifune, Y., Shi, H., Wang, K.W., Zhan, X., Liu, A., Wang, J., et al. (2018). Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti-PD-L1 to eliminate melanoma in mice. Proc. Natl. Acad. Sci. U.S.A. 115, E8698–E8706.PubMedCrossrefGoogle Scholar

  • Weber, A., Kirejczyk, Z., Besch, R., Potthoff, S., Leverkus, M., and Hacker, G. (2010). Proapoptotic signalling through Toll-like receptor-3 involves TRIF-dependent activation of caspase-8 and is under the control of inhibitor of apoptosis proteins in melanoma cells. Cell Death Differ. 17, 942–951.CrossrefPubMedGoogle Scholar

  • WHO (2018). Cancer Fact Sheets. In https://gcoiarcfr/today/fact-sheets-cancers.Google Scholar

  • Wirth, T.C. and Kuhnel, F. (2017). Neoantigen targeting – dawn of a new era in cancer immunotherapy? Front. Immunol. 8, 1848.CrossrefPubMedGoogle Scholar

  • Yadav, M., Jhunjhunwala, S., Phung, Q.T., Lupardus, P., Tanguay, J., Bumbaca, S., Franci, C., Cheung, T.K., Fritsche, J., Weinschenk, T., et al. (2014). Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515, 572–576.CrossrefPubMedGoogle Scholar

  • Yoon, S.I., Kurnasov, O., Natarajan, V., Hong, M., Gudkov, A.V., Osterman, A.L., and Wilson, I.A. (2012). Structural basis of TLR5-flagellin recognition and signaling. Science 335, 859–864.PubMedCrossrefGoogle Scholar

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

  • Zacharski, L.R. and Sukhatme, V.P. (2005). Coley’s toxin revisited: immunotherapy or plasminogen activator therapy of cancer? J. Thromb. Haemost. 3, 424–427.CrossrefPubMedGoogle Scholar

  • Zahringer, U., Lindner, B., Inamura, S., Heine, H., and Alexander, C. (2008). TLR2 – promiscuous or specific? A critical re-evaluation of a receptor expressing apparent broad specificity. Immunobiology 213, 205–224.CrossrefPubMedGoogle Scholar

  • Zaman, M. and Toth, I. (2013). Immunostimulation by synthetic lipopeptide-based vaccine candidates: structure-activity relationships. Front. Immunol. 4, 318.PubMedGoogle Scholar

  • Zaman, M., Abdel-Aal, A.B., Fujita, Y., Phillipps, K.S., Batzloff, M.R., Good, M.F., and Toth, I. (2012). Immunological evaluation of lipopeptide group A streptococcus (GAS) vaccine: structure-activity relationship. PLoS One 7, e30146.CrossrefPubMedGoogle Scholar

  • Zhao, Y., Yang, J., Shi, J., Gong, Y.N., Lu, Q., Xu, H., Liu, L., and Shao, F. (2011). The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477, 596–600.CrossrefPubMedGoogle Scholar

  • Zhu, Q., Egelston, C., Gagnon, S., Sui, Y., Belyakov, I.M., Klinman, D.M., and Berzofsky, J.A. (2010). Using 3 TLR ligands as a combination adjuvant induces qualitative changes in T cell responses needed for antiviral protection in mice. J. Clin. Invest. 120, 607–616.CrossrefGoogle Scholar

About the article

Received: 2019-09-30

Accepted: 2019-11-21

Published Online: 2019-12-13

Citation Information: Biological Chemistry, 20190383, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2019-0383.

Export Citation

©2019 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Comments (0)

Please log in or register to comment.
Log in