title: Antitumor activity of the TLR-5 ligand flagellin in mouse models of cancer.
abstract: Flagellin, the structural protein subunit of the bacterial flagellum, is specifically recognized by TLR-5 and has potent immunomodulatory effects. The antitumor effects of purified Salmonella typhimurium flagellin were evaluated in mice transplanted s.c. with a weakly immunogenic murine tumor or with its variant stably transfected to express the highly antigenic human HER-2 oncoprotein. Peritumoral administration of flagellin 8-10 days after tumor implantation did not affect the growth rate of the weakly immunogenic tumor but significantly inhibited growth of the antigenic variant tumor. In contrast, flagellin administered at the time of implantation of the antigenic tumor led to accelerated tumor growth. These contrasting effects of flagellin on tumor growth correlated with the type of immune response induced; i.e., late flagellin administration was associated with an increased IFN-gamma:IL-4 ratio and the decreased frequency of CD4+CD25+ T regulatory cells, whereas flagellin treatment at the time of tumor implantation decreased the IFN-gamma:IL-4 ratio and increased CD4+CD25+ T cell frequency. When the early flagellin treatment was combined with administration of CpG-containing oligodeoxynucleotides, tumor growth was completely suppressed, indicating synergy between flagellin and CpG-containing oligodeoxynucleotides. Together, these data provide evidence that flagellin can have contrasting effects on tumor growth.
authors.affiliation: Institute of Pathology, University of Milan, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Sfondrini
authors.forename: Anna
authors.initials: A
authors.lastname: Rossini
authors.forename: Dario
authors.initials: D
authors.lastname: Besusso
authors.forename: Andrea
authors.initials: A
authors.lastname: Merlo
authors.forename: Elda
authors.initials: E
authors.lastname: Tagliabue
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mènard
authors.forename: Andrea
authors.initials: A
authors.lastname: Balsari
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005408:Flagellin / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use*; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D008024:Ligands; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000378:metabolism*; D014162:Transfection
chemical_list: D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D008024:Ligands; D051198:Toll-Like Receptor 5; D005408:Flagellin