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,
*
University of Pittsburgh Cancer Institute and Departments of
Pathology and
Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
National Cancer Institute, Bethesda, MD 20892; and
¶
Department of Medical Microbiology, Johannes Gutenberg University, Mainz, Germany
Recently, we observed that CTL specific for the wild-type (wt)
sequence p53264–272 peptide could only be expanded ex vivo
from PBMC of a subset of the HLA-A2.1+ normal donors or
cancer patients tested. Surprisingly, the tumors of the responsive
patients expressed normal levels of wt p53 and could be considered
unlikely to present this epitope. In contrast, tumors of nonresponsive
patients accumulated mutant p53 and were more likely to present this
epitope. We sought to increase the responsive rate to the wt
p53264–272 peptide of PBMC obtained from normal donors and
patients by identifying more immunogenic variants of this peptide. Two
such variants were generated by amino acid exchanges at positions 6
(6T) and 7 (7W) of the peptide. These variants were capable of inducing
T cells from PBMC of nonresponsive donors that recognized the parental
peptide either pulsed onto target cells or naturally presented by
tumors. TCR V
analysis of two T cell lines isolated from bulk
populations of effectors reactive against the wt
p53264–272 peptide, using either the parental or the 7W
variant peptide, indicated that these T cells were expressing identical
TCR V13.6/complementarity-determining region 3/J region sequences.
This finding confirms the heteroclitic nature of at least one of the
variant peptides identified in this study. The use of variant peptides
of the wt p53264–272 epitope represents a promising
approach to overcoming the nonresponsiveness of certain cancer patients
to this self epitope, thereby enhancing its potential use in tumor
vaccines for appropriately selected cancer
patients.
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