Cancer immunotherapeutic potential of novel small molecule TLR7 and TLR8 agonists.
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.
Hamm
Svetlana
S
svetlana.hamm@4sc.com
Rath
Sandra
S
Michel
Susanne
S
Baumgartner
Roland
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D008213:Lymphocyte Activation / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000378:metabolism; D000099192:CD69 Antigens
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D000099192:CD69 Antigens; C111124:SC-1 monoclonal antibody; C477038:Tlr7 protein, mouse