title: Flagellin enhances tumor-specific CD8⁺ T cell immune responses through TLR5 stimulation in a therapeutic cancer vaccine model.
abstract: Tumor antigen (TA)-specific immunotherapy is an emerging approach for cancer treatment. Potent adjuvants are prerequisites to the immunotherapy for overcoming the low immunogenicity of TAs. We previously demonstrated that a bacterial flagellin, Vibrio vulnificus FlaB, has potent adjuvant activity in various vaccination models. In this study, we investigated whether the FlaB protein could be a potent adjuvant for a human papillomavirus 16 E6 and E7 (E6/E7) peptide-based anticancer immunotherapy. We used an E6/E7-expressing TC-1 carcinoma implantation animal model and tested TA-specific immunomodulation by FlaB. We co-administered the E6/E7 peptide either with or without FlaB into TC-1 tumor-bearing mice and then analyzed the antitumor activity of the peptide. FlaB significantly potentiated specific antitumor immune responses elicited by the peptide immunization, as evidenced by retarded in vivo tumor growth and significantly prolonged survival. We noticed that TC-1 cells do not express Toll-like receptor 5 (TLR5) on their surface and the TLR5 signaling pathway in TC-1 cells was not responsible for the antitumor effect of FlaB. FlaB potentiated the CTL activity and Ag-specific IFN-γ production of CD8(+) T cells from the draining lymph node and spleen. In addition, this antitumor activity was abrogated following the in vivo depletion of CD8(+) T cells and in TLR5 knockout (KO) or MyD88 KO mice. These results suggest that flagellin could enhance TA-specific CD8(+) CTL immune responses through TLR5 stimulation in cancer immunotherapy.
authors.affiliation: Clinical Vaccine R&D Center, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Chung Truong
authors.initials: CT
authors.lastname: Nguyen
authors.forename: Seol Hee
authors.initials: SH
authors.lastname: Hong
authors.forename: Jeong-Im
authors.initials: JI
authors.lastname: Sin
authors.forename: Hong Van Dinh
authors.initials: HV
authors.lastname: Vu
authors.forename: Kwangjoon
authors.initials: K
authors.lastname: Jeong
authors.forename: Kyoung Oh
authors.initials: KO
authors.lastname: Cho
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Shee Eun
authors.initials: SE
authors.lastname: Lee
authors.forename: Joon Haeng
authors.initials: JH
authors.lastname: Rhee
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D005260:Female; D005408:Flagellin / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000276:immunology* / Q000378:metabolism; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D051198:Toll-Like Receptor 5; D014614:Vaccines, Synthetic; C059731:oncogene protein E7, Human papillomavirus type 16; D005408:Flagellin; D007371:Interferon-gamma
keywords: Adjuvant; Cancer; Flagellin; TLR5; Vaccine