Summary auto-generated
This study investigated cytotoxic T lymphocyte (CTL) responses to human papillomavirus type 16 (HPV-16) E6 and E7 proteins in cervical cancer patients. Researchers stimulated T cells from an HPV-16-positive cervical carcinoma patient and a healthy volunteer using dendritic cells loaded with synthetic peptides derived from E6 and E7 proteins. Only the E7 peptide (amino acids 86-93) successfully induced low-affinity CTL lines that specifically lysed HLA-A*0201-expressing target cells loaded with this peptide. However, these CTL lines failed to recognize HPV-16 E7-expressing cervical carcinoma cell lines (CaSki, HPK IA) or transfected cells expressing E7 protein. The researchers attributed cytotoxicity against these epithelial cell lines to cross-reactivity on allogeneic HLA molecules rather than genuine E7 recognition. Other E6 and E7 peptides tested did not induce specific CTL responses. The findings emphasize that peptide-induced CTL specificity must be carefully interpreted and highlight the difficulty in generating HPV-specific immune responses in patients with established infections.
Key findings
- Only the HPV-16 E7 peptide (aa 86-93) successfully induced low-affinity CTL lines from both donors; other E6 and E7 peptides failed to generate CTL responses.
- E7/86-93-specific CTL recognized peptide-loaded HLA-A*0201 cells but failed to recognize naturally occurring HPV-16 E7-expressing epithelial cell lines or transfected cells.
- CTL-mediated lysis of cervical carcinoma cells (CaSki, HPK IA) was attributed to cross-reactivity on allogeneic HLA molecules rather than specific E7 recognition.
- The E7/86-93-specific CTL exhibited low affinity, with cytotoxicity disappearing at peptide concentrations of 10 nM.
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Abstract
In order to establish tumour-specific cytotoxic T lymphocyte (CTL) cell lines, T cells from a human papillomavirus (HPV) type 16-positive patient with a cervical carcinoma in situ and from a healthy volunteer were stimulated in vitro with autologous dendritic cells loaded with peptides derived from the viral transforming proteins E6 and E7 and corresponding to potential HLA-A*0201-restricted T cell epitopes. From each donor a small number of low-affinity CTL lines against the peptide E7/86-93 was obtained, which specifically lysed HLA-A*0201-expressing B- lymphocytes (cell line 721) loaded with this peptide. Cytotoxicity was also observed against two HLA-A*0201-E7-positive epithelial cell lines, the cervical carcinoma cell line CaSki and the HPV-16-immortalized foreskin-keratinocyte cell line HPK IA. However, since none of the CTL recognized both cell lines, and E7-expressing 721 transfectants were never lysed, it was concluded that the reactivity against CaSki and HPK IA cells was due to cross-reactivity on allogeneic HLA molecules rather than to E7 recognition, which emphasizes that the specificity of tumour cell lysis by peptide-induced CTL has to be interpreted with caution.