Antitumor activity and immune response induction of a dual agonist of Toll-like receptors 7 and 8.
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.
Idera Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Daqing
D
Wang
Melissa
M
Precopio
Tao
T
Lan
Dong
D
Yu
Jimmy X
JX
Tang
Ekambar R
ER
Kandimalla
Sudhir
S
Agrawal
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D000939:Epitopes / Q000276:immunology; D007109:Immunity / Q000187:drug effects*; D007156:Immunologic Memory / Q000187:drug effects; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009843:Oligoribonucleotides / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051200:Toll-Like Receptor 8 / Q000819:agonists*
D000951:Antigens, Neoplasm; D016207:Cytokines; D000939:Epitopes; D053594:Myeloid Differentiation Factor 88; D009843:Oligoribonucleotides; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D018664:Interleukin-12; D007371:Interferon-gamma