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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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Cervix Uteri / immunology
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Cervix Uteri / metabolism
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Cervix Uteri / virology
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DEAD-box RNA Helicases / metabolism
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Female
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Genital Neoplasms, Female / immunology*
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Genital Neoplasms, Female / metabolism*
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Genital Neoplasms, Female / mortality
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Genital Neoplasms, Female / virology
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Humans
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Immunization
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Interferon-Induced Helicase, IFIH1
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Mice
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Oligodeoxyribonucleotides / administration & dosage
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Oligodeoxyribonucleotides / pharmacology
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Papillomaviridae / immunology*
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Papillomavirus E7 Proteins / immunology
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Papillomavirus Infections / immunology
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Papillomavirus Vaccines / immunology*
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Poly I-C / administration & dosage
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Poly I-C / pharmacology
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Receptors, CCR5 / metabolism
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Receptors, CXCR3 / metabolism
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Receptors, Fibroblast Growth Factor / metabolism
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Sialoglycoproteins / metabolism
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Signal Transduction
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Toll-Like Receptor 3 / metabolism
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Toll-Like Receptors / agonists*
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Toll-Like Receptors / metabolism
Substances
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CPG-oligonucleotide
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Oligodeoxyribonucleotides
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Papillomavirus E7 Proteins
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Papillomavirus Vaccines
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Receptors, CCR5
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Receptors, CXCR3
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Receptors, Fibroblast Growth Factor
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Sialoglycoproteins
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Toll-Like Receptor 3
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Toll-Like Receptors
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cysteine-rich fibroblast growth factor receptor
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oncogene protein E7, Human papillomavirus type 16
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Interferon-gamma
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Ifih1 protein, mouse
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DEAD-box RNA Helicases
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Interferon-Induced Helicase, IFIH1
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Poly I-C