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: Chung Truong Nguyen, Seol Hee Hong, Jeong-Im Sin, Hong Van Dinh Vu, Kwangjoon Jeong, Kyoung Oh Cho, Satoshi Uematsu, Shizuo Akira, Shee Eun Lee, Joon Haeng Rhee
• Journal: Vaccine (Vaccine) Vol. 31 Issue 37 Pg. 3879-87 (Aug 20 2013) ISSN: 1873-2518 [Electronic] Netherlands
• PMID: 23831323 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Adjuvants, Immunologic
• Cancer Vaccines
• E6 protein, Human papillomavirus type 16
• Oncogene Proteins, Viral
• Papillomavirus E7 Proteins
• Repressor Proteins
• Toll-Like Receptor 5
• Vaccines, Synthetic
• oncogene protein E7, Human papillomavirus type 16
• Flagellin
• Interferon-gamma

Topics

• Adjuvants, Immunologic (pharmacology)
• Animals
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cancer Vaccines (genetics, immunology, pharmacology)
• Female
• Flagellin (genetics, immunology, pharmacology)
• Humans
• Interferon-gamma (metabolism)
• Lung Neoplasms (pathology, therapy)
• Mice
• Mice, Inbred C57BL
• Oncogene Proteins, Viral (genetics, immunology)
• Papillomavirus E7 Proteins (genetics, immunology)
• Repressor Proteins (genetics, immunology)
• T-Lymphocytes, Cytotoxic (immunology, metabolism)
• Toll-Like Receptor 5 (immunology, metabolism)
• Vaccines, Synthetic (genetics, immunology, pharmacology)