title: IFN-gamma produced by human papilloma virus-18 E6-specific CD4+ T cells predicts the clinical outcome after surgery in patients with high-grade cervical lesions.
abstract: Cervical neoplastic lesions are associated with infection by high-risk human papilloma viruses (HPVs). HPV-16 and HPV-18 are the most common genotypes. It has been proposed that development of HPV-16-positive cervical lesions is associated with impaired CD4(+) T cell immunity against early Ags. The aim of the study was to evaluate whether this impairment also applies to HPV-18. We investigated the presence and the quality of anti-HPV-18 E6 CD4(+) T cell responses in the blood of 37 consecutive patients with high-grade cervical lesions, 25 normal donors, and 20 cord bloods. The immune infiltrate in the cervical lesions was also evaluated. The characteristics of the responses were correlated to the clinical outcome. We found that one or more HPV-18 E6 peptides, containing naturally processed epitopes, were able to induce a response in 40-50% of the patients, depending on the effector function tested. Importantly, these percentages rose to 80-100% when HPV-18-positive patients were considered. HPV-18 E6-specific CD4(+) T cells produced mixed Th1/Th2 responses and statistical analysis of the cytokines produced revealed that the amount of IFN-gamma released could predict infection persistence and/or disease relapse after surgery. Finally, we found that a higher number of infiltrating CD4(+) and T-bet(+) T cells in the lesions correlated with a favorable clinical outcome. Our results strongly suggest a relevant role for CD4(+) T cells in the control of the HPV-18 compared with HPV-16 infections in patients with high-grade cervical lesions and identify an immunologic parameter potentially useful for patients' stratification.
authors.affiliation: Tumor Immunology Unit, Scientific Institute H. San Raffaele, Milan, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Seresini
authors.forename: Massimo
authors.initials: M
authors.lastname: Origoni
authors.forename: Flavia
authors.initials: F
authors.lastname: Lillo
authors.forename: Luigi
authors.initials: L
authors.lastname: Caputo
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Paganoni
authors.forename: Simone
authors.initials: S
authors.lastname: Vantini
authors.forename: Renato
authors.initials: R
authors.lastname: Longhi
authors.forename: Gianluca
authors.initials: G
authors.lastname: Taccagni
authors.forename: Augusto
authors.initials: A
authors.lastname: Ferrari
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.forename: Piercesare
authors.initials: P
authors.lastname: Secchi
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Protti
mesh_terms: D000328:Adult; D017951:Antigen Presentation / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology*; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology; D052161:Human papillomavirus 18 / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D030361:Papillomavirus Infections / Q000276:immunology* / Q000601:surgery; D010455:Peptides / Q000276:immunology*; D012008:Recurrence; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000601:surgery
chemical_list: D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D010455:Peptides; D007371:Interferon-gamma