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.
OBJECTIVE
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.


METHODS
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, IFN gamma-ELISPOT, and cytokine production and phenotyped by 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 IFN gamma-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.
Welters
Marij J P
MJ
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
Kenter
Gemma G
GG
Piersma
Sytse J
SJ
Vloon
Annelies P G
AP
Löwik
Margriet J G
MJ
Berends-van der Meer
Dorien M A
DM
Drijfhout
Jan W
JW
Valentijn
A Rob P M
AR
Wafelman
Amon R
AR
Oostendorp
Jaap
J
Fleuren
Gert Jan
GJ
Offringa
Rienk
R
Melief
Cornelis J M
CJ
van der Burg
Sjoerd H
SH
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000276:immunology / Q000627:therapeutic use*; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000276:immunology; D010455:Peptides; D012097:Repressor Proteins / Q000276:immunology; D014412:Tumor Virus Infections / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000628:therapy* / Q000821:virology; D014614:Vaccines, Synthetic / Q000276:immunology / Q000627:therapeutic use; D014765:Viral Vaccines / Q000276:immunology / Q000627:therapeutic use*
D019496:Cancer Vaccines; C068651:E6 protein, Human papillomavirus type 16; D015848:Interleukin-5; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D010455:Peptides; D012097:Repressor Proteins; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; C059731:oncogene protein E7, Human papillomavirus type 16; D007371:Interferon-gamma