期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 26, 页码 11895-11899出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1006500107
关键词
human papilloma virus; immunomonitoring; therapeutic vaccine; regulatory T cells
资金
- Dutch Cancer Society [RUL 2007-3848]
- European Union [LSHC-CT-2006-518234]
- European Union Network of Excellence [LSHB-CT-2004-512074]
- ISA Pharmaceuticals B.V.
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 IFN gamma (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 IFN gamma/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-specificCD4(+)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.
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