title: Success or failure of vaccination for HPV16-positive vulvar lesions correlates with kinetics and phenotype of induced T-cell responses.
abstract: One half of a group of 20 patients with human papillomavirus type 16 (HPV16)-induced vulvar intraepithelial neoplasia grade 3 displayed a complete regression (CR) after therapeutic vaccination with HPV16 E6/E7 synthetic long peptides. Patients with relatively larger lesions generally did not display a CR. To investigate immune correlates of treatment failure, patients were grouped according to median lesion size at study entry, and HPV16-specific immunity was analyzed at different time points by complementary immunological assays. The group of patients with smaller lesions displayed stronger and broader vaccine-prompted HPV16-specific proliferative responses with higher IFNgamma (P = 0.0003) and IL-5 (P < 0.0001) levels than patients with large lesions. Characteristically, this response was accompanied by a distinct peak in cytokine levels after the first vaccination. In contrast, the patient group with larger lesions mounted higher frequencies of HPV16-specific CD4(+)CD25(+)Foxp3(+) T cells (P = 0.005) and displayed a lower HPV16-specific IFNgamma/IL-10 ratio after vaccination (P < 0.01). No disparity in T memory immunity to control antigens was found, indicating that the differences in HPV-specific immunity did not reflect general immune failure. We observed a strong correlation between a defined set of vaccine-prompted specific immune responses and the clinical efficacy of therapeutic vaccination. Notably, a high ratio of HPV16-specific vaccine-prompted effector T cells to HPV16-specific CD4(+)CD25(+)Foxp3(+) T cells was predictive of clinical success. Foxp3(+) T cells have been associated previously with impaired immunity in malignancies. Here we demonstrate that the vaccine-prompted level of this population is associated with early treatment failure.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Marij J P
authors.initials: MJ
authors.lastname: Welters
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Kenter
authors.forename: Peggy J
authors.initials: PJ
authors.lastname: de Vos van Steenwijk
authors.forename: Margriet J G
authors.initials: MJ
authors.lastname: Löwik
authors.forename: Dorien M A
authors.initials: DM
authors.lastname: Berends-van der Meer
authors.forename: Farah
authors.initials: F
authors.lastname: Essahsah
authors.forename: Linda F M
authors.initials: LF
authors.lastname: Stynenbosch
authors.forename: Annelies P G
authors.initials: AP
authors.lastname: Vloon
authors.forename: Tamara H
authors.initials: TH
authors.lastname: Ramwadhdoebe
authors.forename: Sytse J
authors.initials: SJ
authors.lastname: Piersma
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: van der Hulst
authors.forename: A Rob P M
authors.initials: AR
authors.lastname: Valentijn
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Fathers
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Kees L M C
authors.initials: KL
authors.lastname: Franken
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostendorp
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Fleuren
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D002278:Carcinoma in Situ / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007700:Kinetics; D008213:Lymphocyte Activation; D030361:Papillomavirus Infections / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D053918:Papillomavirus Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D012074:Remission Induction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D017211:Treatment Failure; D014846:Vulvar Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D053918:Papillomavirus Vaccines