A Wild-type Sequence p53 Peptide Presented by HLA-A24 Induces Cytotoxic T Lymphocytes that Recognize Squamous Cell Carcinomas of the Head and Neck
2000
Evidence
has accumulated indicating that HLA-A2-restricted CTLs specific for
human wild-type sequence p53 epitopes lyse tumor cells expressing
mutant p53. To explore the possibility that wild-type sequence p53
peptides could also be used in vaccines for patients expressing HLA-A24
antigen, another frequent HLA class I allele, we investigated the
induction of HLA-A24-restricted p53-specific CTLs from the peripheral
blood lymphocytes of normal donors. Of six p53-derived peptides
possessing an HLA-A24 binding motif, the p53 peptide 125–134
(p53 125–134 ) was found to have a high binding
capacity and induced peptide-specific CTLs from peripheral blood
mononuclear cells, using peptide-pulsed autologous dendritic cells and
subsequent cultivation with cytokines interleukin 2 and interleukin 7.
Bulk CTL populations lysed peptide-pulsed HLA-A24 + targets
as well as HLA-A24 + squamous cell carcinoma of the head and
neck (SCCHN) cell lines. However, IFN-γ pretreatment of
HLA-A24 + SCCHN cell lines was necessary for lysis,
suggesting that a ligand density higher than that normally expressed by
tumor cells is required for these CTLs to mediate lysis. Moreover, a
cloned CTL, designated TH#99, isolated from the bulk population by
limiting dilution, lysed HLA-A24 + SCCHN targets more
efficiently than the bulk CTL population. Lysis was inhibited by
anti-HLA class I monoclonal antibody but not by anti-HLA-DR monoclonal
antibody. These results indicate that HLA-A24-restricted CTLs
recognizing the wild-type sequence p53 125–134 can be
generated using autologous dendritic cells from precursors present in
peripheral blood lymphocytes obtained from normal HLA-A24 +
donors. This finding suggests that vaccine strategies targeting
wild-type sequence p53 epitopes can be extended to a wider range of
cancer patients.
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