Abstract
We identified a series of immunodominant and subdominant epitopes from alpha fetoprotein (AFP), restricted by HLA-A*0201, which are recognized by the human T cell repertoire. The four immunodominant epitopes have been tested for immunogenicity in vivo, in HLA-A*0201+AFP+ advanced stage hepatocellular cancer (HCC) patients, and have activated and expanded AFP-specific IFN-gamma-producing T cells in these patients, despite high serum levels of this self Ag. Here, we have examined the frequency, function, and avidity of the T cells specific for subdominant epitopes from AFP. We find that T cells specific for several of these epitopes are of similar or higher avidity than those specific for immunodominant epitopes. We then tested the peripheral blood of subjects ex vivo with different levels of serum AFP for the hierarchy of response to epitopes from this Ag and find that HCC patients have detectable frequencies of circulating IFN-gamma-producing AFP-specific CD8+ T cells to both immunodominant and subdominant epitopes. We find the immunodominant and subdominant peptide-specific T cells to be differentially expanded with different modes of Ag presentation. Whereas spontaneous and AFP protein-stimulated responses show evidence for immunodominance, AdVhAFP-transduced dendritic cell-stimulated responses were broader and not skewed. Importantly, these data identify subdominant epitopes from AFP that can activate high-avidity T cells, and that can be detected and expanded in HCC subjects. These subdominant epitope-specific T cells can also recognize tumor cells and may be important therapeutically.
Highlights
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AFP protein-fed GM-CSF/IL-4 dendritic cells (DC), which would approximate AFP-Ag presentation in hepatocellular cancer (HCC) patients with high levels of serum AFP in whom immature DC have taken up circulating protein
Immunotherapy vaccination efforts are designed to provide adequate Ag presentation and to overcome the lack of presentation or inhibitory presentation provided by tumor
Summary
HCC, hepatocellular carcinoma; AFP, ␣ fetoprotein; DC, dendritic cell; IVS, in vitro stimulation. Subsequent murine studies, in which different modes of immunization (plasmid DNA, peptides in adjuvant, AdV) were compared with IFN-␥ ELISPOT readouts, indicated that, AFP158 remained most immunodominant, the immunodominance order varied with immunization strategy for the other three peptides [3]. This was not unexpected, because each method of immunization uses different AFP Ag presentation modes. We have investigated the avidity of subdominant epitope-specific T cells for peptide-pulsed and tumor targets and the hierarchy of CD8 T cell responses to the previously identified immunodominant and subdominant epitopes in subjects with different levels of high serum AFP. We wanted to determine whether HCC subjects have altered hierarchy of responses to this self tumor associated Ag, and more importantly, to determine whether “subdominant” epitopes could be more potent immunogens in these subjects and be the focus of future immunotherapy vaccines
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