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National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
Involvement of tumor-Ag specific CD4+ and
CD8+ T cells could be critical in the generation of an
effective immunotherapy for cancer. In an attempt to optimize the T
cell response against defined tumor Ags, we previously developed a
method allowing transgene expression in human dendritic cells (DCs)
using retroviral vectors. One advantage of using gene-modified DCs is
the potential ability to generate CD8+ T cells against
multiple class I-restricted epitopes within the Ag, thereby eliciting a
broad antitumor immune response. To test this, we generated
tumor-reactive CD8+ T cells with DCs transduced with the
melanoma Ag gp100, for which a number of HLA-A2-restricted epitopes
have been described. Using gp100-transduced DCs, we were indeed able to
raise T cells recognizing three distinct HLA-A2 epitopes within the Ag,
gp100154–162, gp100209–217, and
gp100280–288. We next tested the ability of transduced DCs
to raise class II-restricted CD4+ T cells. Interestingly,
stimulation with gp100-transduced DCs resulted in the generation of
CD4+ T cells specific for a novel
HLA-DR
1*0701-restricted epitope of gp100. The minimal determinant of
this epitope was defined as gp100174–190
(TGRAMLGTHTMEVTVYH). These observations suggest that retrovirally
transduced DCs have the capacity to present multiple MHC class I- and
class II-restricted peptides derived from a tumor Ag, thereby eliciting
a robust immune response against that Ag.
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