Success or failure of vaccination for HPV16-positive vulvar lesions correlates with kinetics and phenotype of induced T-cell responses

Marij J.P. Welters, Gemma G. Kenter, Peggy J. De Vos Van Steenwijk, Margriet J.G. Löwik, Dorien M.A. Berends-van Der Meer, Farah Essahsah, Linda F.M. Stynenbosch, Annelies P.G. Vloon, Tamara H. Ramwadhdoebe, Sytse J. Piersma, Jeanette M. Van Der Hulst, A. Rob P.M. Valentijn, Lorraine M. Fathers, Jan W. Drijfhout, Kees L.M.C. Franken, Jaap Oostendorp, Gert Jan Fleuren, Cornelis J.M. Melief, Sjoerd H. Van Der Burg

Research output: Contribution to journalArticlepeer-review

181 Scopus citations

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 IFNγ (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 IFNγ/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 cellswas 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.

Original languageEnglish
Pages (from-to)11895-11899
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number26
DOIs
StatePublished - Jun 29 2010

Keywords

  • Human papilloma virus
  • Immunomonitoring
  • Regulatory T cells
  • Therapeutic vaccine

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