Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine

Marij J.P. Welters, Gemma G. Kenter, Sytse J. Piersma, Annelies P.G. Vloon, Margriet J.G. Löwik, Dorien M.A. Berends-van Der Meer, Jan W. Drijfhout, A. Rob P.M. Valentijn, Amon R. Wafelman, Jaap Oostendorp, Gert Jan Fleuren, Rienk Offringa, Cornelis J.M. Melief, Sjoerd H. Van Der Burg

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Abstract

Purpose: The study aims to evaluate the effect of a human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides vaccine on the antigen-specific T-cell response in cervical cancer patients. Experimental Design: Patients with resected HPV16-positive cervical cancer were vaccinated with an overlapping set of long peptides comprising the sequences of the HPV16 E6 and E7 oncoproteins emulsified in Montanide ISA-51. HPV16-specific T-cell immune responses were analyzed by evaluating the magnitude, breadth, type, and polarization by proliferation assays, IFNγ-ELISPOT, and cytokine production and phenotypedby the T-cell markers CD4, CD8, CD25, and Foxp3. Results: Vaccine-induced T-cell responses against HPV16 E6 and E7 were detected in six of six and five of six patients, respectively. These responses were broad, involved both CD4+ and CD8+ T cells, and could be detected up to 12 months after the last vaccination. The vaccine-induced responses were dominated by effector type CD4+CD25 +Foxp3- type 1 cytokine IFNγ-producing T cells but also included the expansion of T cells with a CD4+CD25 +Foxp3+ phenotype. Conclusions: The HPV16 E6 and E7 synthetic long peptides vaccine is highly immunogenic, in that it increases the number and activity of HPV16-specific CD4+ and CD8+ T cells to a broad array of epitopes in all patients. The expansion of CD4 + and CD8+ tumor-specific T cells, both considered to be important in the antitumor response, indicates the immunotherapeutic potential of this vaccine. Notably, part of the vaccine-induced T cells display a CD4 +CD25+Foxp3+ phenotype that is frequently associated with regulatory T-cell function, suggesting that strategies to disarm this subset of T cells should be considered as components of immunotherapeutic modalities against HPV-induced cancers.

Original languageEnglish
Pages (from-to)178-187
Number of pages10
JournalClinical Cancer Research
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2008
Externally publishedYes

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    Welters, M. J. P., Kenter, G. G., Piersma, S. J., Vloon, A. P. G., Löwik, M. J. G., Berends-van Der Meer, D. M. A., Drijfhout, J. W., Valentijn, A. R. P. M., Wafelman, A. R., Oostendorp, J., Fleuren, G. J., Offringa, R., Melief, C. J. M., & Van Der Burg, S. H. (2008). Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine. Clinical Cancer Research, 14(1), 178-187. https://doi.org/10.1158/1078-0432.CCR-07-1880