Abstract
Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptors 7 and 8 (TLR7 and TLR8). We have reported a novel class of synthetic oligoribonucleotides, referred to as stabilized immune-modulatory RNA compounds, which act as agonists of TLR7, TLR8, or both TLR7 and TLR8 depending on the sequence composition and the presence of specific chemical modifications. In the present study, we evaluated the antitumor activity of a dual TLR7/8 agonist in tumor-bearing mice with peritoneal disseminated CT26.CL25 colon and 3LL-C75 lung carcinomas. Peritoneal administration of dual TLR7/8 agonist in mice bearing CT26.CL25 colon carcinomas had potent dose-dependent antitumor activity, which was associated with a marked decrease in CD4(+)CD25(+)Foxp3(+) T regulatory cells and a significant increase in tumor antigen-specific IFN-gamma-secreting effector cell responses in splenocytes and local tumor-infiltrating cells. In 3LL-C75 lung carcinoma, dual TLR7/8 agonist induced strong immune responses and antitumor effects in C57BL/6 and TLR9(-/-) mice, but not in TLR7(-/-) and MyD88(-/-) mice, indicating that the agonist induces immune responses via TLR7 and through the MyD88-dependent signaling pathway. TLR8 is not functional in mice. Additionally, s.c. administration of TLR7/8 agonist effectively prevented lung metastasis of tumors in the CT26.CL25 pulmonary metastasis model. These studies show that the dual TLR7/8 agonist induced Th1-type immune responses and potent antitumor activity in mice via TLR7 and through the MyD88-dependent pathway.
Highlights
Toll-like receptors (TLR) recognize specific molecular signatures called pathogen-associated molecular patterns that are present in pathogens
Among the 10 TLRs identified in humans, TLR3, TLR7, TLR8, and TLR9 are expressed in endosomal compartments and detect nucleic acid molecular patterns of viruses and bacteria [1,2,3]
Treatment of CT26.CL25 colon carcinoma–bearing mice with TLR7/8 agonist led to dose-dependent induction of cytokines and increase in survival
Summary
Toll-like receptors (TLR) recognize specific molecular signatures called pathogen-associated molecular patterns that are present in pathogens. Among the 10 TLRs identified in humans, TLR3, TLR7, TLR8, and TLR9 are expressed in endosomal compartments and detect nucleic acid molecular patterns of viruses and bacteria [1,2,3]. Other TLRs are expressed on the cell surface and recognize cell wall constituents of extracellular pathogens. Recent studies suggest that pathogen-associated molecular patterns evoke different immune responses by targeting distinct TLRs and their intracellular adaptor molecules. Bacteria or bacterial-derived molecules such as BCG have long been used as anticancer immunotherapeutic agents [6], recent understanding of TLR-mediated modulation of immune responses has Authors' Affiliation: Idera Pharmaceuticals, Inc., Cambridge, Massachusetts
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