title: Human papillomavirus L1L2-E7 virus-like particles partially mature human dendritic cells and elicit E7-specific T-helper responses from patients with cervical intraepithelial neoplasia or cervical cancer in vitro.
abstract: We evaluated the ability of autologous dendritic cells (DC) pulsed with recombinant human papillomavirus 16 L1L2-E7 virus-like particles (VLPs) to stimulate E7-specific CD4+ T-cell responses from normal donors and patients with cervical intraepithelial neoplasia lesions or cervical carcinoma in vitro. Exposure to VLPs partially matured DCs, as evidenced by upregulated expression of costimulatory and major histocompatibility complex molecules and the reduced capacity of treated DCs to process exogenous antigens. However, VLP treatment failed to promote strong expression of the CD83 or CCR7 markers or to modulate interleukin-12p70 secretion, indicators of terminal DC maturation. Notably, both normal donor- and patient-derived DCs behaved similarly after exposure to VLPs. A single round of in vitro stimulation of CD4+ T cells with DCs exposed to L1L2-E7 VLPs promoted specific anti-E7 responses in the majority of donors. In particular, DCs exposed to VLPs effectively stimulated type 1 biased E7-specific CD4+ T-cell responses in patients with premalignant cervical intraepithelial neoplasia I-III lesions, but type 2 or Treg biased responses in patients with cervical cancer. Given the high rate of CD4+ T-cell responses (14 [93%] of 15 patients) against DC-L1L2-E7 VLP stimulation, this vaccine modality could serve as a foundation for developing a general treatment option for patients with human papillomavirus 16-associated malignancies.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Dominic E
authors.initials: DE
authors.lastname: Warrino
authors.forename: Walter C
authors.initials: WC
authors.lastname: Olson
authors.forename: Meera I
authors.initials: MI
authors.lastname: Scarrow
authors.forename: Lori J
authors.initials: LJ
authors.lastname: D'Ambrosio-Brennan
authors.forename: Richard S
authors.initials: RS
authors.lastname: Guido
authors.forename: Diane M
authors.initials: DM
authors.lastname: Da Silva
authors.forename: W Martin
authors.initials: WM
authors.lastname: Kast
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
mesh_terms: D000328:Adult; D000368:Aged; D017951:Antigen Presentation / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D036022:Capsid Proteins / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006680:HLA Antigens / Q000378:metabolism; D006684:HLA-DR Antigens / Q000276:immunology; D052162:Human papillomavirus 16 / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D021122:Protein Subunits / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000276:immunology*; D002578:Uterine Cervical Dysplasia / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D036022:Capsid Proteins; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D006684:HLA-DR Antigens; D015848:Interleukin-5; C063316:L2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D021122:Protein Subunits; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C059731:oncogene protein E7, Human papillomavirus type 16; D018664:Interleukin-12; C063317:L1 protein, Human papillomavirus type 16; D007371:Interferon-gamma