Human papillomavirus type 16 E6-specific antitumor immunity is induced by oral administration of HPV16 E6-expressing Lactobacillus casei in C57BL/6 mice
- 297 Downloads
Given that local cell-mediated immunity (CMI) against the human papillomavirus type 16 E6 (HPV16 E6) protein is important for eradication of HPV16 E6-expressing cancer cells in the cervical mucosa, the HPV16 E6 protein may be a target for the mucosal immunotherapy of cervical cancer. Here, we expressed the HPV16 E6 antigen on Lactobacillus casei (L. casei) and investigated E6-specific CMI following oral administration of the L. casei-PgsA-E6 to mice. Surface expression of HPV16 E6 antigens was confirmed and mice were orally inoculated with the L. casei-PgsA or the L. casei-PgsA-E6. Compared to the L. casei-PgsA-treated mice, significantly higher levels of serum IgG and mucosal IgA were observed in L. casei-PgsA-E6-immunized mice; these differences were significantly enhanced after boost. Consistent with this, systemic and local CMI were significantly increased after the boost, as shown by increased counts of IFN-γ-secreting cells in splenocytes, mesenteric lymph nodes (MLN), and vaginal samples. Furthermore, in the TC-1 tumor model, animals receiving the orally administered L. casei-PgsA-E6 showed reduced tumor size and increased survival rate versus mice receiving control (L. casei-PgsA) immunization. We also found that L. casei-PgsA-E6-induced antitumor effect was decreased by in vivo depletion of CD4+ or CD8+ T cells. Collectively, these results indicate that the oral administration of lactobacilli bearing the surface-displayed E6 protein induces T cell-mediated cellular immunity and antitumor effects in mice.
KeywordsHPV16 E6 Lactobacillus casei Antitumor effect PgsA Cell-mediated immunity
Poly-gamma-glutamic acid synthetase complex A
Enzyme-linked immunosorbent assay
This work was supported by grants of the Korea Health 21 R&D Project (A050562) and National R&D Program for Cancer Control (0720510), Ministry of Health and Welfare, Republic of Korea and a grant from KRIBB Initiative program to H. Poo.
- 6.Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, Schiffman MH, Moreno V, Kurman R, Shah KV (1995) Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst 87:796–802CrossRefPubMedGoogle Scholar
- 18.Nardelli-Haefliger D, Roden RB, Benyacoub J, Sahli R, Kraehenbuhl JP, Schiller JT, Lachat P, Potts A, De Grandi P (1997) Human papillomavirus type 16 virus-like particles expressed in attenuated Salmonella typhimurium elicit mucosal and systemic neutralizing antibodies in mice. Infect Immun 65:3328–3336PubMedGoogle Scholar
- 23.Hanniffy S, Wiedermann U, Repa A, Mercenier A, Daniel C, Fioramonti J, Tlaskolova H, Kozakova H, Israelsen H, Madsen S, Vrang A, Hols P, Delcour J, Bron P, Kleerebezem M, Wells J (2004) Potential and opportunities for use of recombinant lactic acid bacteria in human health. Adv Appl Microbiol 56:1–64CrossRefPubMedGoogle Scholar
- 28.Kim TY, Myoung HJ, Kim JH, Moon IS, Kim TG, Ahn WS, Sin JI (2002) Both E7 and CpG-oligodeoxynucleotide are required for protective immunity against challenge with human papillomavirus 16 (E6/E7) immortalized tumor cells: involvement of CD4+ and CD8+ T cells in protection. Cancer Res 62:7234–7240PubMedGoogle Scholar
- 33.Manuri PR, Nehete B, Nehete PN, Reisenauer R, Wardell S, Courtney AN, Gambhira R, Lomada D, Chopra AK, Sastry KJ (2007) Intranasal immunization with synthetic peptides corresponding to the E6 and E7 oncoproteins of human papillomavirus type 16 induces systemic and mucosal cellular immune responses and tumor protection. Vaccine 25:3302–3310CrossRefPubMedGoogle Scholar