Cancer immunotherapeutic potential of novel small molecule TLR7 and TLR8 agonists

J Immunotoxicol. 2009 Dec;6(4):257-65. doi: 10.3109/15476910903286733.


Toll-like receptor (TLR)-mediated signaling is proposed as an immunotherapeutic target against tumorigenesis. Natural killer (NK) cells play a critical role in host defense against tumors. Specifically, formation of tumor metastasis in various organs can be suppressed by the local activity of NK cells. In this study, we present a novel TLR7 agonist (termed SC-1) that induces pro-inflammatory cytokines in human blood cells, activates NK cell function, and is highly efficient in preventing lung metastases in a pulmonary metastatic Renca model. Furthermore, a second compound (termed SC-2), acting as dual-specific TLR7 and TLR8 agonist, was evaluated with respect to its immunostimulatory and NK cell-activating capacities. The release of pro-inflammatory cytokines was shown to be even more pronounced with this compound. Additional experiments showed a significant up-regulation of activation marker CD69 on NK cells and increased cytolytic activity of peripheral blood cells compared to the effect of a monospecific TLR7 agonist SC-1. Normally, TLR7 and TLR8 are expressed on different immune cell subpopulations. TLR7 expression on antigen-presenting cells is detected in plasmacytoid dendritic cells, CD34+-derived dendritic cells, and B-cells, whereas TLR8 is mainly expressed on cells of the myeloid lineage, such as monocytes, macrophages, and myeloid dendritic cells. Therefore, a compound that activates both TLR7 and TLR8 would result in a highly efficient immune system activation and may give rise to an enhanced anti-tumor activity in vivo compared to that elicited by a monospecific TLR7 agonist.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Cell Death / drug effects
  • Cell Line
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Immunotherapy
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Lectins, C-Type
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / secondary
  • Lymphocyte Activation / drug effects*
  • Membrane Glycoproteins / agonists*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Toll-Like Receptor 7 / agonists*
  • Toll-Like Receptor 7 / metabolism
  • Toll-Like Receptor 8 / agonists*
  • Toll-Like Receptor 8 / metabolism


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD69 antigen
  • Lectins, C-Type
  • Membrane Glycoproteins
  • SC-1 monoclonal antibody
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8