Identification of promiscuous HPV16-derived T helper cell epitopes for therapeutic HPV vaccine design.
Cervical carcinoma and several other human papillomavirus (HPV)-induced malignancies are a global public health problem, thus novel treatment modalities are urgently needed. Immunotherapy is an attractive option for treatment of HPV infection and HPV-mediated premalignant and malignant lesions. However, previous approaches--focusing on the induction of cytotoxic CD8+ T cells (CTLs)--have as yet not yielded clinical successes. Since CD4+ T cells have been shown to be crucial for the induction and maintenance of CTL responses, and more recently to be also important for direct anti-tumor immunity, human leukocyte antigen (HLA) class II-restricted epitopes are intensively investigated to improve the efficacy of peptide-based HPV immunotherapy. We here present an approach to identify promiscuous HPV16-derived CD4+ T helper epitopes, which are capable of inducing T cell immunity in a large proportion of the population. To this end, we combined HLA class II epitope prediction servers with in vitro immunological evaluation to identify HPV16 E2-, E5-, E6-, and E7-derived CD4+ T cell epitopes. Candidate selected HPV16-derived epitopes were found to be restricted by up to nine HLA-DR molecules. Furthermore, they were found to induce frequent and robust HPV16 peptide-specific Th1 responses in healthy donors, as monitored by interferon (IFN)-γ ELISPOT and cytokine secretion assays. Moreover, these selected peptides also induced specific IFN-γ T cell responses in blood from HPV16+ CIN2/3 and cervical carcinoma patients. We thus conclude that the identified T helper epitopes are valuable candidates for the development of a comprehensive therapeutic HPV vaccine.
Immunotherapy and -prevention, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Agnieszka K
AK
Grabowska
Andreas M
AM
Kaufmann
Angelika B
AB
Riemer
D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D019496:Cancer Vaccines / Q000276:immunology; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D030361:Papillomavirus Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D014611:Vaccination; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology; D002578:Uterine Cervical Dysplasia / Q000276:immunology / Q000517:prevention & control* / Q000821:virology
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D014764:Viral Proteins
CD4+ T cell epitope; CD4+ T cell immunity; cervical cancer; human papillomavirus; tumor immunotherapy