title: Intravaginal TLR agonists increase local vaccine-specific CD8 T cells and human papillomavirus-associated genital-tumor regression in mice.
abstract: Human papillomaviruses (HPV)-related cervical cancer is the second leading cause of cancer death in women worldwide. Despite active development, HPV E6/E7 oncogene-specific therapeutic vaccines have had limited clinical efficacy to date. Here, we report that intravaginal (IVAG) instillation of CpG-ODN (TLR9 agonist) or poly-(I:C) (TLR3 agonist) after subcutaneous E7 vaccination increased ~fivefold the number of vaccine-specific interferon-γ-secreting CD8 T cells in the genital mucosa (GM) of mice, without affecting the E7-specific systemic response. The IVAG treatment locally increased both E7-specific and total CD8 T cells, but not CD4 T cells. This previously unreported selective recruitment of CD8 T cells from the periphery by IVAG CpG-ODN or poly-(I:C) was mediated by TLR9 and TLR3/melanoma differentiation-associated gene 5 signaling pathways, respectively. For CpG, this recruitment was associated with a higher proportion of GM-localized CD8 T cells expressing both CCR5 and CXCR3 chemokine receptors and E-selectin ligands. Most interestingly, IVAG CpG-ODN following vaccination led to complete regression of large genital HPV tumors in 75% of mice, instead of 20% with vaccination alone. These findings suggest that mucosal application of immunostimulatory molecules might substantially increase the effectiveness of parenterally administered vaccines.
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Domingos-Pereira
authors.forename: L
authors.initials: L
authors.lastname: Decrausaz
authors.forename: L
authors.initials: L
authors.lastname: Derré
authors.forename: M
authors.initials: M
authors.lastname: Bobst
authors.forename: P
authors.initials: P
authors.lastname: Romero
authors.forename: J T
authors.initials: JT
authors.lastname: Schiller
authors.forename: P
authors.initials: P
authors.lastname: Jichlinski
authors.forename: D
authors.initials: D
authors.lastname: Nardelli-Haefliger
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002584:Cervix Uteri / Q000276:immunology / Q000378:metabolism / Q000821:virology; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D005260:Female; D005833:Genital Neoplasms, Female / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000821:virology; D006801:Humans; D007114:Immunization; D000072640:Interferon-Induced Helicase, IFIH1; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology; D027383:Papillomaviridae / Q000276:immunology*; D050725:Papillomavirus E7 Proteins / Q000276:immunology; D030361:Papillomavirus Infections / Q000276:immunology; D053918:Papillomavirus Vaccines / Q000276:immunology*; D011070:Poly I-C / Q000008:administration & dosage / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D012795:Sialoglycoproteins / Q000378:metabolism; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism
chemical_list: C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D017468:Receptors, Fibroblast Growth Factor; D012795:Sialoglycoproteins; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; C086711:cysteine-rich fibroblast growth factor receptor; C059731:oncogene protein E7, Human papillomavirus type 16; D007371:Interferon-gamma; C510592:Ifih1 protein, mouse; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C